Pyridine and pyrimidine derivatives

ABSTRACT

Compounds of formula (1) are described in which R a  and R b  is each independently a hydrogen atom or a group R c , or R a  and R b  together form an oxo (═O) or thio (═S) group; X is a N atom or an optionally substituted CH group: Y is a —O— or —S— atom or —SO— or —SO 2 — group or an optionally substituted —CH 2 — or —NH— group with the proviso that when R a  and R b  together form an oxo (═O) or thio (═S) group Y is an optionally substituted —CH 2 — or —NH-group; L 1  is a covalent bond or a linker atom or group; p is zero or the integer 1; Alk 1  is an optionally substituted C 1-10 aliphatic or C 1-10 heteroaliphatic chain; n is zero the integer 1, 2 or 3 with the proviso that when n is zero Y is an optionally substituted —CH 2 — group: Ar is an optionally substituted C 6-12 aromatic or C 1-9 heteroaromatic group; m is zero or the integer 1, 2 or 3; q is zero or the integer 1 or 2; R 1 , R c  and R d  are hydrogen atoms or the substituents described in the patent specification; and the salts, solvates, hydrates and N-oxides thereof. The compounds are potent and selective inhibitors of p38 kinase and are useful in the treatment of immune or inflammatory disorders.

This invention relates to a series of pyridine and pyrimidinederivatives, to compositions containing them, to processes for theirpreparation and to their use in medicine.

Immune and inflammatory responses involve a variety of cell types withcontrol and co-ordination of the various interactions occurring via bothcell-cell contacts (e.g integrin interactions with their receptors) andby way of intercellular signalling molecules. A large number ofdifferent signalling molecules are involved including cytokines,lymphocytes, chemokines and growth factors.

Cells respond to such intercellular signalling molecules by means ofintracellular signalling mechanisms that include protein kinases,phosphatases and phospholipases. There are five classes of proteinkinase of which the major ones are the tyrosine kinases and theserine/threonine kinases [Hunter, T., Methods in Enzymology (ProteinKinase Classification) p. 3, Hunter, T. and Sefton, B. M.; eds. Vol.200, Academic Press; San Diego, 1991].

One sub-class of serine/threonine kinases is the mitogen activatingprotein (MAP) kinases of which there are at least three families whichdiffer in the sequence and size of the activation loop [Adams, J. L. etal, Progress in Medicinal Chemistry p. 1-60, King, F. D. and Oxford, A.W.; eds. vol 38, Elsevier Science, 2001]: the extracellular regulatedkinases (ERKs), the c-Jun NH₂ terminal kinases or stress activatedkinases (JNKs or SAP kinases) and the p38 kinases which have athreonine-glycine-tyrosine (TGY) activation motif. Both the JNKs and p38MAP kinases are primarily activated by stress stimuli including, but notlimited to, proinflammatory cytokines e.g. tumour nucrosis factor (TNF)and interleukin-1 (IL-1), ultraviolet light, endotoxin and chemical orosmotic shock.

Four isoforms of p38 have been described (p38α/β/γ/δ). The human p38αenzyme was initially identified as a target of cytokine-suppressiveanti-inflammatory drugs (CSAIDs) and the two isoenzymes found wereinitially termed CSAID binding protein-1 (CSBP-1) and CSBP-2 [Lee, J. C.et al, Nature (London) 1994, 372, 739-46]. CSBP-2 is now widely referredto as p38α and differs from CSBP-1 in an internal sequence of 25 aminoacids as a result of differential splicing of two exons that areconserved in both mouse and human [McDonnell, P. C. et al, Genomics1995, 29, 301-2]. CSBP-1 and p38α are expressed ubiquitously and thereis no difference between the two isoforms with respect to tissuedistribution, activation profile, substrate preference or CSAID binding.A second isoform is p38β which has 70% identity with p38α. A second formof p38β termed p38β2 is also known and of the two this is believed to bethe major form. p38α and p38β2 are expressed in many different tissues.However in monocytes and macrophages p38α is the predominant kinaseactivity [Lee, J. C., ibid; Jing, Y. et al, J. Biol. Chem. 1996, 271,10531-34; Hale, K. K. et al, J. Immun. 1999, 162, 4246-52]. p38γ andp38δ (also termed SAP kinase-3 and SAP kinase-4 respectively) have ˜63%and ˜61% homology to p38α respectively. p38γ is predominantly expressedin skeletal muscle whilst p38δ is found in testes, pancreas, prostate,small intestine and in certain endocrine tissues.

All p38 homologues and splice variants contain a 12 amino acidactivation loop that includes a Thr-Gly-Tyr motif. Dual phosphorylationof both Thr-180 and Tyr-182 in the TGY motif by a dual specificityupstream kinase is essential for the activation of p38 and results ina >1000-fold increase in specific activity of these enzymes [Doza, Y. N.et al FEBS Lett., 1995, 364, 7095-8012]. This dual phosphorylation iseffected by MKK6 and under certain conditions the related enzyme MKK3(see FIG. 1) [Enslen, H. et al J. Biol. Chem., 1998, 273, 1741-48]. MKK3and MKK6 belong to a family of enzymes termed MAPKK (mitogen activatingprotein kinase kinase) which are in turn activated by MAPKKK (mitogenactivating kinase kinase kinase) otherwise known as MAP3K.

Several MAP3Ks have been identified that are activated by a wide varietyof stimuli including environmental stress, inflammatory cytokines andother factors. MEKK4/MTK1 (MAP or ERK kinase kinase/MAP three kinase-1),ASK1 (apoptosis stimulated kinase) and TAK1 (TGF-β-activated kinase) aresome of the enzymes identified as upstream activators of for MAPKKs.MEKK4/MTK1 is thought to be activated by several GADD-45-like genes thatare induced in response to environmental stimuli and which eventuallylead to p38 activation [Takekawa, M. and Saito, H. Cell, 1998, 95,521-30]. TAK1 has been shown to activate MKK6 in response totransforming growth factor-β (TGF-β). TNF-stimulated activation of p38is believed to be mediated by the recruitment of TRAF2 [TNF receptorassociated factor] and the Fas adaptor protein, Daxx, which results inthe activation of ASK1 and subsequently p38.

Several substrates of p38 have been identified including other kinases[e.g. MAPK activated protein kinase 2/3/5 (MAPKAP 2/3/5), p38regulated/activated protein kinase (PRAK), MAP kinase-interacting kinase1/2 (MNK1/2), mitogen- and stress-activated protein kinase 1 (MSK1/RLPK)and ribosomal S6 kinase-B (RSK-B)], transcription factors [e.g.activating transcription factor 2/6 (ATF2/6), monocyte-enhancerfactor-2A/C (MEF2A/C), C/EBP homologous protein (CHOP), Elk1 andSap-1a1] and others substrates [e.g. cPLA2, p47phox].

MAPKAP K2 is activated by p38 in response to environmental stress. Miceengineered to lack MAPKAP K2 do not produce TNF in response tolipopolysaccharide (LPS). Production of several other cytokines such asIL-1, IL-6, IFN-g and IL-10 is also partially inhibited [Kotlyarov, A.et al Nature Cell Biol. 1999, 1, 94-7]. Further, MAPKAP K2 fromembryonic stem cells from p38α null mice was not activated in responseto stress and these cells did not produce IL-6 in response to IL-1[Allen, M. et al, J. Exp. Med. 2000, 191, 859-69]. These resultsindicate that MAPKAP K2 is not only essential for TNF and IL-1production but also for signalling induced by cytokines. In additionMAPKAP K2/3 phosphorylate and thus regulate heat shock proteins HSP 25and HSP 27 which are involved in cytoskeletal reorganization.

Several small molecule inhibitors of p38 have been reported whichinhibit IL-1 and TNF synthesis in human monocytes at concentrations inthe low μM range [Lee, J. C. et al, Int. J. Immunopharm. 1988, 10, 835]and exhibit activity in animal models which are refractory tocyclooxygenase inhibitors [Lee, J. C. et al, Annals N. Y. Acad. Sci.1993, 696, 149]. In addition these small molecule inhibitors are knownto also decrease the synthesis of a wide variety of pro-inflammatoryproteins including IL-6, IL-8, granulocyte/macrophage colony-stimulatingfactor (GM-CSF) and cyclooxygenase-2 (COX-2). TNF-inducedphosphorylation and activation of cytosolic PLA2, TNF-induced expressionof VCAM-1 on endothelial cells and IL-1 stimulated synthesis ofcollagenase and stromelysin are also inhibited by such small moleculeinhibitors of p38 [Cohen, P. Trends Cell Biol. 1997, 7, 353-61].

A variety of cells including monocytes and macrophages produce TNF andIL-1. Excessive or unregulated TNF production is implicated in a numberof disease states including Crohn's disease, ulcerative colitis,pyresis, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis,gouty arthritis and other arthritic conditions, toxic shock syndrome,endotoxic shock, sepsis, septic shock, gram negative sepsis, boneresporption diseases, reperfusion injury, graft vs. host reaction,allograft rejection, adult respiratory distress syndrome, chronicpulmonary inflammatory disease, silicosis, pulmonary sarcoisosis,cerebral malaria, scar tissue formation, keloid formation, fever andmyalias due to infection, such as influenza, cachexia secondary toacquired immune deficiency syndrome (AIDS), cachexia secondary toinfection or malignancy, AIDS or AIDS related complex.

Excessive or unregulated IL-1 production has been implicated inrheumatoid arthritis, osteoarthritis, traumatic arthritis, rubellaarthritis, acute synovitis, psoriatic arthritis, cachexia, Reiter'ssyndrome, endotoxemia, toxic shock syndrome, tuberculosis,atherosclerosis, muscle degeneration, and other acute or chronicinflammatory diseases such as the inflammatory reaction induced byendotoxin or inflammatory bowel disease. In addition IL-1 has beenlinked to diabetes and pancreatic β cells [Dinarello, C. A. J. ClinicalImmunology, 1985, 5, 287-97].

IL-8 is a chemotactic factor produced by various cell types includingendothelial cells, mononuclear cells, fibroblasts and keratinocytes.IL-1, TNF and LPS all induce the production of IL-8 by endothelialcells. In vitro IL-8 has been shown to have a number of functionsincluding being a chemoattractant for neutrophils, T-lymphocytes andbasophils. IL-8 has also been shown to increase the surface expressionof Mac-1 (CD11b/CD18) on neutrophils without de novo protein synthesiswhich may contribute to increased adhesion of neutrophils to vascularendothelial cells. Many diseases are characterised by massive neutrophilinfiltration. Histamine release from basophils (in both atopic andnormal individuals) is induced by IL-8 as is lysozomal enzyme releaseand respiratory burst from neutrophils.

The central role of IL-1 and TNF together with other leukocyte derivedcytokines as important and critical inflammatory mediators is welldocumented. The inhibition of these cytokines has been shown or would beexpected to be of benefit in controlling, alleviating or reducing manyof these disease states.

The central position that p38 occupies within the cascade of signallingmolecules mediating extracellular to intracellular signalling and itsinfluence over not only IL-1, TNF and IL-8 production but also thesynthesis and/or action of other pro-inflammatory proteins (e.g. IL-6,GM-CSF, COX-2, collagenase and stromelysin) make it an attractive targetfor inhibition by small molecule inhibitors with the expectation thatsuch inhibition would be a highly effective mechanism for regulating theexcessive and destructive activation of the immune system. Such anexpectation is supported by the potent and diverse anti-inflammatoryactivities described for p38 kinase inhibitors [Adams, ibid; Badger, etal, J. Pharm. Exp. Ther. 1996, 279, 1453-61; Griswold, et al, Pharmacol.Comm., 1996, 7, 323-29].

We have now found a group of compounds which are potent and selectiveinhibitors of p38 kinase (p38α, β, δ and γ) and the isoforms and splicevariants thereof, especially p38α, p38β and p38β2. The compounds arethus of use in medicine, for example in the prophylaxis and treatment ofimmune or inflammatory disorders as described herein.

SUMMARY OF THE INVENTION

Thus according to one aspect of the invention we provide a compound offormula (1):

wherein:

-   -   R^(a) and R^(b) is each independently a hydrogen atom or a group        R^(c), or R^(a) and R^(b) together form an oxo (═O) or thio (═S)        group;    -   X is a N atom or an optionally substituted CH group;    -   Y is a —O— or —S— atom or —SO— or —SO₂— group or an optionally        substituted —CH₂— or —NH— group with the proviso that when R^(a)        and R^(b) together form an oxo (═O) or thio (═S) group Y is an        optionally substituted —CH₂— or —NH— group;    -   L¹ is a covalent bond or a linker atom or group;    -   p is zero or the integer 1;    -   Alk¹ is an optionally substituted C₁₋₁₀aliphatic or        C₁₋₁₀heteroaliphatic chain;    -   R¹ is a hydrogen or halogen atom or a —CN, —NO₂ or optionally        substituted C₃₋₁₀cycloaliphatic, C₇₋₁₀polycycloaliphatic,        C₂₋₁₀heterocycloaliphatic, C₆₋₁₀heteropolycycloaliphatic,        C₆₋₁₂aromatic or C₁₋₉heteroaromatic group, with the proviso that        when L¹ is a covalent bond and p is zero R¹ is other than a        hydrogen or halogen atom or a —CN or —NO₂ group;    -   n is zero the integer 1, 2 or 3 with the proviso that when n is        zero Y is an optionally substituted —CH₂— group;    -   Ar is an optionally substituted C₆₋₁₂aromatic or        C₁₋₉heteroaromatic group;    -   m is zero or the integer 1, 2 or 3;    -   R^(c), which may be present on any carbon or, where available,        nitrogen atom in the Y-containing ring, is an oxo (═O) or thio        (═S) atom or an atom or group —(Alk²)_(r)(R⁵)_(s) in which Alk²        is an optionally substituted C₁₋₁₀aliphatic or        C₁₋₁₀heteroaliphatic chain, r is zero or the integer 1, s is the        integer 1, 2 or 3 and R⁵ is a hydrogen or halogen atom or a,        hydroxyl (—OH), thiol (—SH), cyano (—CN), —CO₂R² (where R² is a        hydrogen atom or an optionally substituted C₁₋₆alkyl,        C₆₋₁₂aromatic or C₁₋₉heteroaromatic group), —OCO₂R², —CONR²R³        (where R³ is a hydrogen atom or an optionally substituted        C₁₋₆alkyl group or together with the N atom to which they are        attached R² and R³ alkyl groups are joined to form a        heterocyclic ring which may be optionally interrupted by a        further —O— or —S— atom or —N(R²)— group), —OCONR²R³, —CSNR²R³,        nitro (—NO₂), amino (—NH₂), —NHR², —N(R²)(R³), —COR², —OCOR²,        —N(R³)COR², —N(R³)CSR², —SO₂N(R²)(R³), —N(R²)SO₂R³,        —N(R⁴)CON(R²)(R³) (where R⁴ is a hydrogen atom or an optionally        substituted C₁₋₆alkyl group), —N(R⁴)CSN(R²)(R³),        —N(R⁴)SO₂N(R²)(R³), C₃₋₁₀cycloaliphatic,        C₂₋₁₀heterocycloaliphatic, C₆₋₁₂aromatic or C₁₋₉heteroaromatic        group;    -   q is zero or the integer 1, 2 or 3;    -   R^(d) is a hydrogen or halogen atom or a C₁₋₈alkyl,        haloC₁₋₆alkyl, hydroxyl (—OH), C₁₋₆alkoxy, haloC₁₋₆alkoxy, thiol        (—SH), C₁₋₆alkylthio, cyano (—CN), —CO₂R⁶ (where R⁶ is a        hydrogen atom or an optionally substituted C₁₋₆alkyl group),        —OCO₂R⁶, —CONR⁶R⁷ (where R⁷ is a hydrogen atom or an optionally        substituted C₁₋₆alkyl group or together with the N atom to which        they are attached R⁶ and R⁷ alkyl groups are joined to form a        heterocyclic ring which may be optionally interrupted by a        further —O— or —S— atom or —N(R⁶)— group), —OCONR⁶R⁷, —CSNR⁶R⁷,        nitro (—NO₂), amino(—NH₂), —NHR⁶, —N(R⁶)(R⁷), —COR⁶, —OCOR⁶,        —N(R⁷)COR⁶, —N(R⁷)CSR⁶, —SO₂N(R⁶)(R⁷), —N(R⁶)SO₂R⁷,        —N(R⁸)CON(R⁶)(R⁷) (where R⁸ is a hydrogen atom or an optionally        substituted C₁₋₆alkyl group), —N(R⁸)CSN(R⁶)(R⁷) or        —N(R⁸)SO₂N(R⁶)(R⁷) group; and the salts, solvates, hydrates and        N-oxides thereof;

It will be appreciated that compounds of formula (1) may have one ormore chiral centres, and exist as enantiomers or diastereomers. Theinvention is to be understood to extend to all such enantiomers,diastereomers and mixtures thereof, including racemates. Formula (1) andthe formulae hereinafter are intended to represent all individualisomers and mixtures thereof, unless stated or shown otherwise. Inaddition, compounds of formula (1) may exist as tautomers, for exampleketo (CH₂C═O)-enol (CH═CHOH) tautomers. Formula (1) and the formulaehereinafter are intended to represent all individual taulomers andmixtures thereof, unless stated otherwise.

The following general terms as used herein have the stated meaningunless specifically described otherwise.

As used herein the term ”C₁₋₆alkyl” whether present as a group or partof a group includes straight or branched C₁₋₆alkyl groups, for exampleC₁₋₄alkyl groups such as methyl, ethyl, n-propyl, i-propyl, n-butyl,s-butyl, i-butyl or t-butyl groups. Similarly, the terms “alkenyl” or“alkynyl” are intended to mean straight or branched C₂₋₆alkenyl orC₂₋₆alkynyl groups such as C₂₋₄alkenyl or C₂₋₄alkynyl groups. Optionalsubstituents which may be present on these groups include those optionalsubstituents mentioned hereinafter in relation to Alk¹ when Alk¹ is anoptionally substituted aliphatic chain.

The term halogen is intended to include fluorine, chlorine, bromine oriodine atoms.

The term “haloalkyl” is intended to include those alkyl groups justmentioned sustituted by one, two or three of the halogen atoms justdescribed. Particular examples of such groups include —CF₃, —CCl₃,—CHF₂, —CHCl₂, —CH₂F and —CH₂Cl groups.

The term “C₁₋₆alkoxy” as used herein is intended to include straight orbranched C₁₋₆alkoxy e.g. C₁₋₄alkoxy such as methoxy, ethoxy, n-propoxy,i-propoxy, n-butoxy, s-butoxy, i-butoxy and t-butoxy. “Haloalkoxy” asused herein includes any of these alkoxy groups substituted by one, twoor three halogen atoms as described above. Particular examples include—OCF₃, —OCCl₃, —OCHF₂, —OCHCl₂, —OCH₂F and —OCH₂Cl groups.

As used herein the term “C₁₋₆alkylthio” is intended to include straightor branched C₁₋₆alkylthio, e.g. C₁₋₄alkylthio such as methylthio orethylthio.

As used herein the term “alkylamino or dialkylamino” is intended toinclude the groups —NHR⁹ and —N(R⁹)₂ [where R⁹ is an optionallysubstituted straight or branched C₁₋₆alkyl group]. Where two R⁹ groupsare present these may be the same or different. In addition where two R⁹groups are present these may be joined together with the N atom to whichthey are attached to form an optionally substituted heterocycloalkylgroup which may contain a further heteroatom or heteroatom containinggroup such as an —O— or —S— atom or —N(R⁹)— group. Particular examplesof such optionally substituted heterocycloalkyl groups includeoptionally substituted piperidinyl, pyrazolidinyl, morpholinyl,thiomorpholinyl, pyrrolidinyl, imidazolidinyl and piperazinyl groups.The optional substituents which may be present on such heterocycloalkylgroups include C₁₋₆alkyl groups or those optional substituents asdescribed hereinafter in relation to aliphatic chains.

When Alk¹ is present in compounds of formula (1) as an optionallysubstituted aliphatic chain it may be an optionally substitutedC₁₋₁₀aliphatic chain. Particular examples include optionally substitutedstraight or branched chain C₁₋₆alkylene, C₂₋₆alkenylene, orC₂₋₆alkynylene chains.

Particular examples of aliphatic chains represented by Alk¹ includeoptionally substitute a —CH₂—, —CH(CH₃)—, —CH₂CH₂—, —CH(CH₃)CH₂—,—(CH₂)₂CH₂—, —(CH₂)₃CH₂—, —CH(CH₃)(CH₂)₂CH₂—, —CH₂CH(CH₃)CH₂—,—C(CH₃)₂CH₂—, —CH₂C(CH₃)₂CH₂—, —(CH₂)₂CH(CH₃)CH₂—, —CH(CH₃)CH₂CH₂—,—CH(CH₃)CH₂CH(CH₃)CH₂—, —CH₂CH(CH₃)CH₂CH₂—, —(CH₂)₂C(CH₃)₂—,—(CH₂)₄CH₂—, —(CH₂)₅CH₂—, —CHCH—, —CHCHCH₂—, —CH₂CHCH—, —CHCHCH₂CH₂—,—CH₂CHCHCH₂—, —(CH₂)₂CHCH—, —CC—, —CCCH₂—, —CH₂CC—, —CCCH₂CH₂—,—CH₂CCCH₂— or —(CH₂)₂CCH— chains.

Heteroaliphatic chains represented by Alk¹ in the compounds of formula(1) include the aliphatic chains just described but with eachadditionally containing one, two, three or four heteroatoms orheteroatom-containing groups. Particular heteroatoms or groups includeatoms or groups L² where L² is a linker atom or group. Each L² atom orgroup may interrupt the aliphatic group, or may be positioned at itsterminal carbon atom to connect the group to an adjoining atom or group.Particular examples include optionally substituted -L²CH₂—, —CH₂L²-,-L²CH(CH₃)—, —CH(CH₃)L²-, —CH₂L²CH₂—, -L²CH₂CH₂—, -L²CH₂CH(CH₃)—,—CH(CH₃)CH₂L²-, —CH₂CH₂L²-, —CH₂L²CH₂CH₂—, —CH₂L²CH₂CH₂L²-,—(CH₂)₂L²CH₂—, —(CH₂)₃L²CH₂—, -L²(CH₂)₂CH₂—, -L²CH₂CHCH—, —CHCHCH₂L²-and —(CH₂)₂L²CH₂CH₂— chains.

When L² is present in heteroaliphatic chains as a linker atom or groupit may be any divalent linking atom or group. Particular examplesinclude —O— or —S— atoms or —C(O)—, —C(O)O—, —OC(O)—, —C(S)—, —S(O)—,—S(O)₂—, —N(R¹⁰)— [where R¹⁰ is a hydrogen atom or a straight orbranched C₁₋₆alkyl group], —N(R¹⁰)O—, —N(R¹⁰)N—, —CON(R¹⁰)—,—OC(O)N(R¹⁰)—, —CSN(R¹⁰)—, —N(R¹⁰)CO—, —N(R¹⁰)C(O)O—, —N(R¹⁰)CS—,—S(O)₂N(R¹⁰)—, —N(R¹⁰)S(O)₂—, —N(R¹⁰)CON(R¹⁰)—, —N(R¹⁰)CSN(R¹)— or—N(R¹⁰)SO₂N(R¹⁰)— groups. Where L² contains two R¹⁰ groups these may bethe same or different.

The optional substituents which may be present on aliphatic orheteroaliphatic chains represented by Alk¹ include one, two, three ormore substituents where each substituent may be the same or differentand is selected from halogen atoms, e.g. fluorine, chlorine, bromine oriodine atoms, or —OH, ═CO₂H, —CO₂R¹¹ [where R¹¹ is an optionallysubstituted straight or branched C₁₋₆alkyl group], e.g. —CO₂CH₃ or—CO₂C(CH₃)₃, —CONHR¹¹, e.g. —CONHCH₃, —CON(R¹¹)₂, e.g. —CON(CH₃)₂,—COR¹, e.g. —COCH₃, C₁₋₆alkoxy, e.g. methoxy or ethoxy, haloC₁₋₆alkoxy,e.g. trifluoromethoxy or difluoromethoxy, thiol (—SH), —S(O)R¹¹, e.g.—S(O)CH₃, —S(O)₂R¹¹, e.g. —S(O)₂CH₃, C₁₋₆alkylthio e.g. methylthio orethylthio, amino, —NHR¹¹, e.g. —NHCH₃ or —N(R¹¹)₂, e.g. —N(CH₃)₂ groups.Where two R¹¹ groups are present in any of the above substituents thesemay be the same or different.

In addition when two R¹¹ alkyl groups are present in any of the optionalsubstituents just described these groups may be joined, together withthe N atom to which they are attached, to form a heterocyclic ring ashereinbefore defined when two R⁹ groups are so joined.

When L¹ is present in compounds of formula (1) as a linker atom or groupit may be any such atom or group as hereinbefore described in relationto L² linker atoms and groups.

Optionally substituted cycloaliphatic groups represented by the group R¹in compounds of the invention include optionally substitutedC₃₋₁₀cycloaliphatic groups. Particular examples include optionallysubstituted C₃₋₁₀cycloalkyl, e.g. C₃₋₇cycloalkyl or C₃₋₁₀cycloalkenyl,e.g C₃₋₇cycloalkenyl groups.

Optionally substituted heterocycloaliphatic group represented by thegroup R¹ include optionally substituted C₂₋₁₀heterocycloaliphatic group.Particular examples include optionally substitutedC₂₋₁₀heterocycloalkyl, e.g. C₂₋₇heterocycloalkyl orC₂₋₁₀heterocycloalkenyl, e.g. C₂₋₇heterocycloalkenyl groups, each ofsaid groups containing one, two, three or four heteroatoms or heteroatomcontaining groups L³ in place of or in addition to the ring carbon atomswhere L³ is an atom or group as previously defined for L².

Optionally substituted polycycloaliphatic groups represented by thegroup R¹ include optionally substituted C₇₋₁₀bi-or tricycloalkyl orC₇₋₁₀bi- or tricycloalkenyl groups. Optionally substitutedheteropolycycloaliphatic groups represented by the group R¹ includeoptionally substituted C₆₋₁₀bi- or tricycloalkyl or C₆₋₁₀bi- ortri-cycloalkenyl groups containing one, two, three, four or more L³atoms or groups in place of or in addition to the ring carbon atoms.

Particular examples of cycloaliphatic, polycycloaliphatic,heterocycloaliphatic and heteropolycycloaliphatic groups represented bythe group R¹ include optionally substituted cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, 2-cyclobuten-1-yl,2-cyclopenten-1-yl, 3-cyclopenten-1-yl, adamantyl, norbornyl,norbornenyl, oxiranyl, oxetanyl, aziridinyl, azetidinyl, dihydrofuranyl,tetrahydrofuranyl, tetrahydropyranyl, dihydrothiophenyl,tetrahydrothiophenyl, pyrroline, e.g. 2- or 3-pyrrolinyl, pyrrolidinyl,pyrrolidinone, oxazolidinyl, oxazolidinone, dioxolanyl, e.g.1,3-dioxolanyl, imidazolinyl, e.g. 2-imidazolinyl, imidazolidinyl,pyrazolinyl, e.g. 2-pyrazolinyl, pyrazolidinyl,5,6-dihydro-2(1H)-pyrazinone, tetrahydropyrimidinyl, thiazolinyl,thiazolidinyl, pyranyl, e.g. 2- or 4-pyranyl, piperidinyl,homopiperidinyl, heptamethyleneiminyl, piperidinone, 1,4-dioxanyl,morpholinyl, morpholinone, 1,4-dithianyl, thiomorpholinyl, piperazinyl,homopiperazinyl, 1,3,5-trithianyl, oxazinyl, e.g. 2H-1,3-, 6H-1,3-,6H-1,2-, 2H-1,2- or 4H-1,4-oxazinyl, 1,2,5-oxathiazinyl, isoxazinyl,e.g. o- or p-isoxazinyl, oxathiazinyl, e.g. 1,2,5 or 1,2,6-oxathiazinyl,1,3,5-oxadiazinyl, dihydroisothiazolyl, dihydroisothiazole 1,1-dioxide ,e.g. 2,3-dihydroisothiazole 1,1-dioxide, dihydropyrazinyl andtetrahydropyrazinyl groups.

The optional substituents which may be present on the cycloaliphatic,polycycloaliphatic, heterocycloaliphatic or heteropolycycloaliphaticgroups represented by the group R¹ include one, two, three or moresubstituents selected from halogen atoms, or C₁₋₆alkyl, e.g. methyl orethyl, haloC₁₋₆alkyl, e.g. halomethyl or haloethyl such asdifluoromethyl or trifluoromethyl, optionally substituted by hydroxyl,e.g. —C(OH)(CF₃)₂, C₁₋₆alkoxy, e.g. methoxy or ethoxy, haloC₁₋₆alkoxy,eg. halomethoxy or haloethoxy such as difluoromethoxy ortrifluoromethoxy, thiol, C₁₋₆alkylthiol, e.g. methylthiol or ethylthiol,carbonyl (═O), thiocarbonyl (═S), imino (═NR¹²) [where R¹² is an —OHgroup or a C₁₋₆alkyl group], or —(Alk³)_(v)R¹³ groups in which Alk³ is astraight or branched C₁₋₃alkylene chain, v is zero or the integer 1 andR¹³ is a C₃₋₈cycloalkyl, —OH, —SH, —N(R¹⁴)(R¹⁵) [in which R¹⁴ and R¹⁵ iseach independently selected from a hydrogen atom or an optionallysubstituted C₁₋₆alkyl or C₃₋₈cycloalkyl group, or together with the Natom to which they are attached R¹⁴ and R¹⁵ alkyl groups are joined toform a heterocyclic ring which may be optionally interrupted by afurther —O— or —S— atom or —N(R¹⁴)— group as hereinbefore defined whentwo R⁹ groups are joined to form a heterocyclic ring], —OR¹⁴, —SR¹⁴,—CN, —NO₂, —CO₂R¹⁴, —SOR¹⁴, —SO₂R¹⁴, —SO₃R¹⁴, —OCO₂R¹⁴, —C(O)R¹⁴,—OC(O)R¹⁴, —C(S)R¹⁴, —C(O)N(R¹⁴)(R¹⁵), —OC(O)N(R¹⁴)(R¹⁵),—N(R¹⁴)C(O)R¹⁵, —C(S)N(R¹⁴)(R¹⁵), —N(R¹⁴)C(S)R¹⁵, —SO₂N(R¹⁴)(R¹⁵),—N(R¹⁴)SO₂R¹⁵, —N(R¹⁶)C(O)N(R¹⁴)(R¹⁵) [where R¹⁶ is a hydrogen atom or aC₁₋₆alkyl group], —N(R¹⁶)C(S)N(R¹⁴)(R¹⁵), —N(R¹⁶)SO₂N(R¹⁴)(R¹⁵) or anoptionally substituted C₆₋₁₂aromatic or C₁₋₉heteroaromatic group.

Particular examples of Alk³ chains include —CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—,—CH₂CH(CH₃)—, and —CH(CH₃)CH₂— chains.

When R¹³, R¹⁴ and/or R¹⁵ is present as a C₃₋₈cycloalkyl groups it may befor example a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group.Optional substituents which may be present on such groups include forexample one, two or three substituents which may be the same ordifferent selected from halogen atoms, for example fluorine, chlorine,bromine or iodine atoms, or hydroxy or C₁₋₆alkoxy, e.g. methoxy, ethoxyor i-propoxy groups.

When R² and R³, R⁶ and R⁷ or R¹⁴ and R¹⁵ are each alkyl groups joinedtogether with the N atom to which they are attached to form aheterocyclic ring they may be any such ring as hereinbefore describedwhen two R⁹ alkyl groups are so joined.

When R⁵ is an optionally substituted C₆₋₁₂aromatic or C₁₋₉heteroaromaticgroup it may be any such group as described hereinafter in relation toR¹.

Additionally, when the group R¹ is a heterocycloaliphatic orheteropolycycloaliphatic group containing one or more nitrogen atomseach nitrogen atom may be optionally substituted by a group-L⁴(Alk⁴)_(h)R¹⁷ in which L⁴ is a covalent bond or a —C(O)—, —C(O)O—,—C(S)—, —S(O)₂—, —CON(R¹⁰)— or —SO₂N(R¹⁰)— group; Alk⁴ is an optionallysubstituted aliphatic or heteroaliphatic chain; h is zero or the integer1; and R¹⁷ is a hydrogen atom or an optionally substitutedcycloaliphatic, heterocycloaliphatic, polycycloaliphatic,heteropolycycloaliphatic, aromatic or heteroaromatic group as hereindescribed in relation to R¹.

When Alk⁴ is present as an aliphatic or heteroaliphatic chain it may befor example any aliphatic or heteroaliphatic chain as hereinbeforedescribed for Alk¹.

Optionally substituted aromatic groups represented by the groups R¹include for example monocyclic or bicyclic fused ring C₆₋₁₂aromaticgroups, such as phenyl, 1- or 2-napthyl, 1- or 2-tetrahydronapthyl,indanyl or indenyl groups.

Heteroaromatic groups represented by the groups R¹ include for exampleC₁₋₉heteroaromatic groups containing for example one, two, three or fourheteroatoms selected from oxygen, sulphur or nitrogen atoms. In general,the heteroaromatic groups may be for example monocyclic or bicyclicfused-ring heteroaromatic groups. Monocyclic heteroaromatic groupsinclude for example five- or six-membered heteroaromatic groupscontaining one, two, three or four heteroatoms selected from oxygen,sulphur or nitrogen atoms. Bicyclic heteroaromatic groups include forexample eight- to thirteen-membered fused ring heteroaromatic groupscontaining one, two or more heteroatoms selected from oxygen, sulphur ornitrogen atoms.

Particular examples of heteroaromatic groups of these types includepyrrolyl, furyl, thienyl, imidazolyl, N-C₁₋₆alkylimidazolyl, oxazolyl,isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, 1,2,3-triazolyl,1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl, 1,3,4-thiadiazolyl, pyridyl, pyrimidinyl,pyridazinyl, pyrazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl,1,2,3-triazinyl, benzofuryl, [2,3-dihydro]benzofuryl, benzothienyl,[2,3-dihydro]benzothienyl, benzotriazolyl, indolyl, indolinyl,indazolinyl, benzimidazolyl, imidazo[1,2-a]pyridyl, benzothiazolyl,benzoxazolyl, benzisoxazolyl, benzopyranyl, [3,4-dihydro]benzopyranyl,quinazolinyl, quinoxalinyl, naphthyridinyl, imidazo[1,5-a]pyridinyl,imidazo[1,5-a]pyrazinyl, imidazo[1,5-c]pyrimidinyl,pyrido[3,4-b]pyridyl, pyrido[3,2-b]pyridyl, pyrido[4,3-b]pyridyl,quinolinyl, isoquinolinyl, phthalazinyl, tetrazolyl,5,6,7,8-tetrahydroquinolinyl, 5,6,7,8-tetrahydroisoquinolinyl, imidyl,e.g. succinimidyl, phthalimidyl or naphthalimidyl such as1,8-naphthalimidyl, pyrazolo[4,3-d]pyrimidinyl, furo[3,2-d]pyrimidinyl,thieno[3,2-d]pyrimidinyl, pyrrolo[3,2-d]pyrimidinyl,pyrazolo[3,2-b]pyridinyl, furo[3,2-b]pyridinyl, thieno[3,2-b]pyridinyl,pyrrolo[3,2-b]pyridinyl, thiazolo[3,2-a]pyridinyl,pyrido[1,2-a]pyrimidinyl, tetrahydroimidazo[1,2-a]pyrimidinyl anddihydroimidazo[1,2-a]pyrimidinyl groups.

Optional substituents which may be present on aromatic or heteroaromaticgroups represented by the group R¹ include one, two, three or moresubstituents, each selected from an atom or group R¹⁸ in which R¹⁸ isR^(18a) or -L⁵(Alk⁵)_(f)(R^(18a))_(g), where R^(18a) is a halogen atom,or an amino (—NH₂), substituted amino, nitro, cyano, hydroxyl (—OH),substituted hydroxyl, formyl, carboxyl (—CO₂H), esterified carboxyl,thiol (—SH), substituted thiol, —COR¹⁹ [where R¹⁹ is an-L⁵(Alk⁵)_(f)(R^(18a))_(g), aryl or heteroaryl group], —CSR₁₉, —SO₃H,—SOR¹⁹, —SO₂R¹⁹, —SO₃R¹⁹, —SO₂NH₂, —SO₂NHR¹⁹, —SO₂N(R¹⁹)₂, —CONH₂,—CSNH₂, —CONHR¹⁹, —CSNHR¹⁹, —CON(R¹⁹)₂, —CSN(R¹⁹)₂, —N(R²⁰)SO₂R¹⁹ [whereR²⁰ is a hydrogen atom or a straight or branched C₁₋₆alkyl group],—N(SO₂R¹⁹)₂, —N(R²⁰)SO₂NH₂, —N(R²⁰)SO₂NHR¹⁹, —N(R²⁰)SO₂N(R¹⁹)₂,—N(R²⁰)COR¹⁹, —N(R²⁰)CONH₂, —N(R²⁰)CONHR¹⁹, —N(R²⁰)CON(R¹⁹)₂,—N(R²⁰)CSNH₂, —N(R²⁰)CSNHR¹⁹, —N(R²)CSN(R¹⁹)₂, —N(R²⁰)CSR¹⁹,—N(R²)C(O)OR¹⁹, —SO₂NHet¹ [where —NHet¹ is an optionally substitutedC₅₋₇cyclicamino group optionally containing one or more other —O— or —S—atoms or —N(R²⁰)—, —C(O)— or —C(S)— groups], —CONHet¹, —CSNHet¹,—N(R²⁰)SO₂NHet¹, —N(R²⁰)CONHet¹, —N(R²⁰)CSNHet¹, —SO₂N(R²⁰)Het (where-Het is an optionally substituted monocyclic C₅₋₇carbocyclic groupoptionally containing one or more other —O— or —S— atoms or —N(R²⁰)—,—C(O)—, —S(O)— or —S(O)₂— groups], -Het, —CON(R²⁰)Het, —CSN(R²⁰)Het,—N(R²⁰)CON(R²⁰)Het, —N(R²⁰)CSN(R²⁰)Het, —N(R²⁰)SO₂N(R²⁰)Het, aryl orheteroaryl groups; L⁵ is a covalent bond or a linker atom or group ashereinbefore defined for L²; f is zero or the integer 1; Alk⁵ is anoptionally substituted straight or branched C₁₋₆alkylene, C₂₋₆alkenyleneor C₂₋₆alkynylene chain, optionally interrupted by one, two or three —O—or —S— atoms or —S(O)_(n)— [where n is an integer 1 or 2] or —N(R²⁰)—e.g. —N(CH₃)— groups; and g is zero or the integer 1, 2, or 3. It willbe appreciated that when two R¹⁹ or R²⁰ groups are present in one of theabove substituents the R¹⁹ and/or R²⁰ groups may be the same ordifferent.

When in the group -L⁵Alk⁵(R^(18a))_(g) g is an integer 1, 2 or 3, it isto be understood is that the substituent or substituents R^(18a) may bepresent on any suitable carbon atom in -Alk⁵. Where more than oneR^(18a) substituent is present these may be the same or different andmay be present on the same or different atom in -Alk⁵. Clearly, when gis zero and no substituent R^(18a) is present the alkylene, alkenyleneor alkynylene chain represented by Alk⁵ becomes an alkyl, alkenyl oralkynyl group.

When R^(18a) is a substituted amino group it may be for example a group—NHR⁹ [where R⁹ is as defined above] or a group —N(R)₂ wherein each R⁹group is the same or different.

When R^(18a) is a halogen atom it may be for example a fluorine,chlorine, bromine, or iodine atom.

When R^(18a) is a substituted hydroxyl or substituted thiol group it maybe for example a group —OR¹⁹ or a R¹⁹ group respectively.

Esterified carboxyl groups represented by the group R^(18a) includegroups of formula —CO₂Alk⁶ wherein Alk⁶ is a straight or branched,optionally substituted C₁₋₈alkyl group such as a methyl, ethyl,n-propyl, i-propyl, n-butyl, i-butyl, s-butyl or t-butyl group; aC₆₋₁₂arylC₁₋₈alkyl group such as an optionally substituted benzyl,phenylethyl, phenylpropyl, 1-naphthylmethyl or 2-naphthylmethyl group; aC₆₋₁₂aryl group such as an optionally substituted phenyl, 1-naphthyl or2-naphthyl group; a C₆₋₁₂aryloxyC₁₋₈alkyl group such as an optionallysubstituted phenyloxymethyl, phenyloxyethyl, 1-naphthyloxymethyl, or2-naphthyloxymethyl group; an optionally substitutedC₁₋₈alkanoyloxyC₁₋₈alkyl group, such as a pivaloyloxymethyl,propionyloxyethyl or propionyloxypropyl group; or aC₆₋₁₂aroyloxyC₁₋₈alkyl group such as an optionally substitutedbenzoyloxyethyl or benzoyloxypropyl group. Optional substituents presenton the Alk⁶ group include R^(10a) atoms and groups as described above.

When Alk⁵ is present in or as a substituent it may be for example a—CH₂—, —CH(CH₃)—, —C(CH₃)₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, —CH(CH₃)CH₂—,—CH₂CH₂CH₂CH₂—, —CH₂CH(CH₃)CH₂—, —CH(CH₃)CH₂CH₂—, —C(CH₃)₂CH₂—, —CH═CH—,—CH═CCH₂—, —CH₂C═CH—, —CH═CHCH₂CH₂—, —CH₂CH═CHCH₂—, —CH₂CH₂CH═CH₂—,—CC—, —CCCH₂—, —CH₂CC—, —CCCH₂CH₂—, —CH₂CCCH₂— or —CH₂CH₂CC— chain,optionally interrupted by one, two, or three —O— or —S—, atoms or—S(O)—, —S(O)₂— or —N(R₂)—, e.g. —N(CH₃)— groups. The aliphatic chainsrepresented by Alk⁵ may be optionally substituted by one, two or threehalogen atoms in addition to any R^(18a) groups that may be present.

Aryl or heteroaryl groups represented by the groups R^(18a) or R¹⁹include mono- or bicyclic optionally substituted C₆₋₁₂aromatic orC₁₋₉heteroaromatic groups as described hereinbefore for the group R¹.The aromatic and heteroaromatic groups may be attached to the group R¹in compounds of formula (1) by any carbon or hetero e.g. nitrogen atomas appropriate.

It will be appreciated that when —NHet¹ or -Het forms part of asubstituent R¹⁸ the heteroatoms or heteroatom containing groups that maybe present within the ring —NHet¹ or -Het take the place of carbon atomswithin the parent carbocyclic ring.

Thus when —NHet¹ or -Het forms part of a substituent R^(18a) each may befor example an optionally substituted pyrrolidinyl, imidazolidinyl,pyrazolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, piperidinyl orthiazolidinyl group. Additionally -Het may represent for example, anoptionally substituted cyclopentyl or cyclohexyl group. Optionalsubstituents which may be present on —NHet¹ or -Het include thosesubstituents described above when R¹ is a heterocycloaliphatic group.

Particularly useful atoms or groups represented by R¹⁸ include fluorine,chlorine, bromine or iodine atoms, or C₁₋₆alkyl, e.g. methyl, ethyl,n-propyl, i-propyl, n-butyl or t-butyl, optionally substituted phenyl,pyridyl, pyrimidinyl, pyrrolyl, furyl, thiazolyl, or thienyl,C₁₋₆hydroxyalkyl, e.g. hydroxymethyl or hydroxyethyl, carboxyC₁₋₆alkyl,e.g. carboxyethyl, C₁₋₆alkylthio e.g. methylthio or ethylthio,carboxyC₁₋₆alkylthio, e.g. carboxymethylthio, 2-carboxyethylthio or3-carboxy-propylthio, C₁₋₆alkoxy, e.g. methoxy or ethoxy,hydroxyC₁₋₆alkoxy, e.g. 2-hydroxyethoxy, optionally substituted phenoxy,pyridyloxy, thiazolyoxy, phenylthio or pyridylthio, C₃₋₇cycloalkyl, e.g.cyclobutyl, cyclopentyl, C₅₋₇cycloalkoxy, e.g. cyclopentyloxy,haloC₁₋₆alkyl, e.g. trifluoromethyl, haloC₁₋₆alkoxy, e.g.trifluoromethoxy, C₁₋₆alkylamino, e.g. methylamino, ethylamino,—CH(CH₃)NH₂ or —C(CH₃)₂NH₂, haloC₁₋₆alkylamino, e.g.fluoroC₁₋₆alkylamino,e.g. —CH(CF₃)NH₂ or —(CF₃)₂NH₂, amino (—NH₂),aminoC₁₋₆alkyl, e.g. aminomethyl or aminoethyl, C₁₋₆dialkylamino, e.g.dimethylamino or diethylamino, C₁₋₆alkylaminoC₁₋₆alkyl, e.g.ethylaminoethyl, C₁₋₆dialkylaminoC₁₋₆alkyl, e.g. diethylaminoethyl,aminoC₁₋₆alkoxy, e.g. aminoethoxy, C₁₋₆alkylaminoC₁₋₆alkoxy, e.g.methylaminoethoxy, C₁₋₆dialkylaminoC₁₋₆alkoxy, e.g. dimethylaminoethoxy,diethylaminoethoxy, diisopropylaminoethoxy, or dimethylaminopropoxy,imido, such as phthalimido or naphthalimido, e.g. 1,8-naphthalimido,nitro, cyano, hydroxyl (—OH), formyl [HC(O)—], carboxyl (—CO₂H),—CO₂Alk⁶ [where Alk⁶ is as defined above], C₁₋₆ alkanoyl e.g. acetyl,optionally substituted benzoyl, thiol (—SH), thioC₁₋₆alkyl, e.g.thiomethyl or thioethyl, sulphonyl (—SO₃H), C₁₋₆alkylsulphonyl, e.g.methylsulphonyl, aminosulphonyl (—SO₂NH₂), C₁₋₆alkylaminosulphonyl, e.g.methylaminosulphonyl or ethylaminosulphonyl, C₁₋₆dialkylaminosulphonyl,e.g. dimethylaminosulphonyl or diethylaminosulphonyl,phenylaminosulphonyl, carboxamido (—CONH₂), C₁₋₆alkylaminocarbonyl, e.g.methylaminocarbonyl or ethylaminocarbonyl, C₁₋₆dialkylaminocarbonyl,e.g. dimethylaminocarbonyl or diethylaminocarbonyl,aminoC₁₋₆alkylaminocarbonyl, e.g. aminoethylamino-carbonyl,C₁₋₆dialkylaminoC₁₋₆alkylaminocarbonyl, e.g.diethylaminoethylaminocarbonyl, aminocarbonylamino,C₁₋₆alkylaminocarbonylamino, e.g. methylaminocarbonylamino orethylaminocarbonylamino, C₁₋₆dialkylaminocarbonylamino, e.g.dimethylaminocarbonylamino or diethylaminocarbonylamino,C₁₋₆alkylaminocabonylC₁₋₆alkylamino, e.g.methylaminocarbonylmethylamino, aminothiocarbonylamino,C₁₋₆alkylaminothiocarbonylamino, e.g. methylaminothiocarbonylamino orethylaminothiocarbonylamino, C₁₋₆dialkylaminothiocarbonylamino, e.g.dimethylaminothiocarbonylamino or diethylaminothiocarbonylamino,C₁₋₆alkylaminothiocarbonylC₁₋₆alkylamino, e.g.ethylaminothiocarbonylmethylamino, —CONHC(═NH)NH₂,C₁₋₆alkylsulphonylamino, e.g. methylsulphonylamino orethylsulphonylamino, C₁₋₆dialkylsulphonylamino, e.g.dimethylsulphonylamino or diethylsulphonylamino, optionally substitutedphenylsulphonylamino, aminosulphonylamino (—NHSO₂NH₂),C₁₋₆alkylaminosulphonylamino, e.g. methylaminosulphonylamino orethylaminosulphonylamino, C₁₋₆dialkylaminosulphonylamino, e.g.dimethylaminosulphonylamino or diethylaminosulphonylamino, optionallysubstituted morpholinesulphonylamino ormorpholinesulphonylC₁₋₆alkylamino, optionally substitutedphenylaminosulphonylamino, C₁₋₆alkanoylamino, e.g. acetylamino,aminoC₁₋₆alkanoylamino e.g. aminoacetylamino,C₁₋₆dialkylaminoC₁₋₆alkanoylamino, e.g. dimethylaminoacetylamino,C₁₋₆alkanoylaminoC₁₋₆alkyl, e.g. acetylaminomethyl,C₁₋₆alkanoylaminoC₁₋₆alkylamino, e.g. acetamidoethylamino,C₁₋₆alkoxycarbonylamino, e.g. methoxycarbonylamino, ethoxycarbonylaminoor t-butoxycarbonylamino or optionally substituted benzyloxy,pyridylmethoxy, thiazolylmethoxy, benzyloxycarbonylamino,benzyloxycarbonylaminoC₁₋₆alkyl e.g. benzyloxycarbonylaminoethyl,benzothio, pyridylmethylthio or thiazolylmethylthio groups.

A further particularly useful group of substituents represented by R¹⁸when present on aromatic or heteroaromatic groups includes substituentsof formula -L⁵Alk⁵R^(18a) where L⁵ is preferably a covalent bond or an—O— or —S— atom or —N(R¹⁰)—, —C(O)—, —C(O)O—, —O—C(O)—, —N(R¹⁰)CO—,—CON(R²)— or —N(R¹⁰)S(O)₂— group, Alk⁶ is an optionally substitutedC₁₋₆alkyl group optionally interrupted by one or two —O— or —S— atoms or—N(R²⁰)—, —C(O)—, —C(S)—, —CON(R²⁰)— or —N(R²⁰)CO— groups and R^(18a) isan optionally substituted Het group as herein defined or an optionallysubstituted C₁₋₉heteroaromatic group as hereinbefore described inrelation to R¹.

Where desired, two R¹⁸ substituents may be linked together to form acyclic group such as a cyclic ether, e.g. a C₁₋₆alkylenedioxy group suchas methylenedioxy or ethylenedioxy.

It will be appreciated that where two or more R¹⁸ substituents arepresent, these need not necessarily be the same atoms and/or groups. Ingeneral, the substituent(s) may be present at any available ringposition on the aromatic or heteroaromatic group represented by thegroup R¹.

When Ar is present in compounds of formulae (1) as an optionallysubstituted aromatic or heteroaromatic group it may be any such group ashereinbefore described for R¹. Optional substituents which may bepresent include those R¹⁸ atoms and groups as described in relation toR¹ aromatic and heteroaromatic groups.

When in compounds of formula (1) Y is an optionally substituted —CH₂— or—NH— group the substituents which may be present on the N or C atom inplace of hydrogen atoms include those R^(c) atoms and groups as hereindefined.

When Alk² is present in a substituent R^(c) as an optionally substitutedC₁₋₁₀aliphatic or C₁₋₁₀heteroaliphatic chain it may be any such chain ashereinbefore defined for Alk¹.

When R⁵ is present in a substituent R^(c) as an optionally substitutedC₃₋₁₀cycloaliphatic, C₂₋₁₀heterocycloaliphatic, C₆₋₁₂aromatic orC₁₋₉heteroaromatic group it may be any such group as hereinbeforedefined for R¹.

When R² s present in a substituent R^(c) as an optionally substitutedC₆₋₁₂aromatic or C₁₋₉heteroaromatic group it may be any such group ashereinbefore defined for R¹.

When in compounds of formula (1) X is an optionally substituted —CH—group the substituents which may be present on the C atom in place ofthe hydrogen atom include those R^(d) atoms and groups as hereindefined.

One useful group of compounds according to the invention is that whereR^(a) and R^(b) is each independently a hydrogen atom or together forman oxo (═O) or thio (═S) group most preferably an oxo group.

An especially useful group of compounds according to the invention hasthe formula (2):

in which

-   -   J is an oxygen or sulphur atom;    -   Y is an optionally substituted —CH₂— or —NH— group;    -   R¹, Alk¹, p, L¹, Ar, R^(c), m, R^(d), q and n are as generally        and specifically defined previously;    -   and the salts, solvates, hydrates and N-oxides thereof.

In compounds of formula (2) Y is an optionally substituted —CH₂— or —NH—group. In one preferred group of compounds of formula (2) Y is anoptionally substituted —NH— group where preferred optional substituentsare straight or branched C₁₋₄alkyl groups, especially —CH₃, CH₂CH₃,—CH₂CH₂CH₃ or —CH(CH₃)₂ groups. Most preferably Y is a —NH— group.

In one preferred class of compounds of formula (1) and (2) n is theinteger 1.

In a preferred class of compounds of formula (2) J is an oxygen atom. Incompounds of this type, Y is preferably a —NH— or —N(CH₃)— group.

In compounds of formula (2) and in general in compounds of the inventionL¹ is preferably a covalent bond or an —O— or —S— atom or an —N(R¹⁰)—,especially —NH— or —N(CH₃)—, —C(O)—, —C(S)—, —S(O)— or —S(O)₂— group andis especially a covalent bond or an —O— or —S— atom or —NH— group. Inparticular L¹ is a —NH— group in compounds of the invention.

In one preferred class of compounds of the invention p is zero.

In another preferred class of compounds of the invention p is theinteger 1 and Alk¹ is preferably an optionally substituted C₁₋₆alkylenechain, especially a —CH₂—, —CH(CH₃)—, —C(CH₃)₂—, —CH₂CH₂—, —CH₂CH₂CH₂—,—CH(CH₃)CH₂— or —CH₂CH(CH₃)— chain, most especially a —CH₂—, —CH(CH₃)—or —C(CH₃)₂— chain.

In compounds of formula (2) and in general in compounds of the inventionR¹ is preferably a hydrogen atom or an optionally substitutedC₃₋₁₀cycloaliphatic, C₂₋₁₀heterocycloaliphatic, C₆₋₁₂aromatic orC₁₋₉heteroaromatic group.

Particularly preferred R¹ optionally substituted cycloaliphatic groupsinclude optionally substituted C₃₋₇cycloalkyl groups, especiallycyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl groups. Particularlypreferred optional substituents which may be present on such groupsinclude halogen atoms, especially fluorine, chlorine or bromine atoms,or C₁₋₆alkyl groups, especially C₁₋₄alkyl groups, most especially amethyl group, or a haloC₁₋₆alkyl group, especially a fluoroC₁₋₆alkylgroup, most especially a —CF₃ group, or a C₁₋₆alkoxy, especiallymethoxy, ethoxy, propxy or i-propoxy group, or a haloC₁₋₆alkoxy,especially a fluoroC₁₋₆alkoxy, most especially a OCF₃ group, or a cyano(—CN), nitro (—NO₂), substituted amino, especially —NHCH₃ or —N(CH₃)₂, —or COR¹¹, especially —COCH₃, group.

Particularly preferred R¹ optionally substituted heterocycloaliphaticgroups include optionally substituted C₂₋₇heterocycloalkyl groupscontaining one or two —O— or —S— atoms or —N(R¹⁰)— groups, especiallytetrahydrofuranyl, tetrahydropyranyl, imidazolidinyl, piperidinyl,morpholinyl, thiomorpholinyl, or piperazinyl groups. Optionalsubstituents which may be present on such groups include those optionalsubstituents as just described in relation to preferred R¹cycloaliphatic groups.

Particularly preferred R¹ aromatic groups include optionally substitutedphenyl groups. Particularly preferred heteroaromatic groups includeoptionally substituted monocyclic heteroaromatic groups, especiallyoptionally substituted five- or six-membered heteroaromatic groupscontaining one, two, three or four heteroatoms selected from oxygen,sulphur or nitrogen atoms. Particularly preferred optionally substitutedmonocyclic heteroaromatic groups include optionally substituted furyl,thienyl, pyrrolyl, oxazolyl, thiazolyl, pyridyl, pyrimidinyl ortriazinyl group.

Particularly preferred optional substituents which may be present on R¹aromatic or heteroaromatic groups include atoms or groups —R^(18a) or-L⁵Alk⁵(R^(18a))_(g) as hereinbefore defined. Particularly usefuloptional substituents include halogen atoms, especially fluorine,chlorine or bromine atoms, or C₁₋₆alkyl groups, especially C₁₋₄alkylgroups, most especially a methyl group, or haloC₁₋₆alkyl groups,especially a fluoroC₁₋₆alkyl group, most especially a —CF₃ group, orC₁₋₆alkoxy, especially methoxy, ethoxy, propxy or i-propoxy groups, orhaloC₁₋₆alkoxy, especially fluoroC₁₋₆alkoxy, most especially —OCF₃groups, or cyano (—CN), esterified carboxyl, especially —CO₂CH₃ or—CO₂C(CH₃)₃, nitro (—NO₂), amino (—NH₂), substituted amino, especially—NHCH₃ or —N(CH₃)₂, —COR¹⁹, especially —COCH₃, or —N(R²⁰)COR¹⁹,especially —NHCOCH₃ groups.

In one particularly preferred class of compounds of formula (1) and (2)L¹ is a covalent bond. In this group of compounds p is preferably zeroand R¹ is preferably an optionally substituted C₂₋₇heterocycloalkylgroup as just defined, especially a N atom containingC₂₋₇heterocycloalkyl group, most preferably a piperidinyl, morpholinyl,thiomorpholinyl or piperidinyl group, especially linked via a ring Natom to the remainder of the compound of formula (1) or (2). Optionalsubstituents which may be present on such groups include thosesubstituents as just described for preferred R¹ cycloaliphatic groups.

In another particularly preferred class of compounds of formula (1) and(2) L¹ is a preferred atom or group as just described, especially an —O—or —S— atom or —N(R¹⁰)—, especially —NH— group. In one preferred groupof compounds of this class p is the integer 1 and Alk¹ is preferably anoptionally substituted C₁₋₆alkylene chain as just described. In thisgroup of compounds R¹ is preferably a hydrogen atom. In anotherpreferred group of compounds of this class p is the integer 1 and Alk¹is preferably an optionally substituted C₁₋₃alkylene chain, where thepreferred optional substituents are those just described for Alk¹. Mostpreferably Alk¹ is a —CH₂—, —CH(CH₃)—, —C(CH₃)₂—, —CH₂CH₂—, —CH₂CH₂CH₂—,—CH(CH₃)CH₂— or —CH₂CH(CH₃)-— chain. In this class of compounds R¹ ispreferably an optionally substituted C₃₋₁₀cycloaliphatic,C₂₋₁₀heterocycloaliphatic, C₆₋₁₂aromatic or C₁₋₉heteroaromatic group asherein generally and particularly described. In this class of compoundsR¹ is most preferably an optionally substituted C₆₋₁₂aromatic,especially optionally substituted phenyl group as just described.

In another particularly preferred class of compounds of formula (1) and(2) L¹ is a prefer ed atom or group as just described, especially an —O—or —S— atom or —N(R¹⁰)—, especially —NH— group. In this class ofcompounds p is preferably zero and R¹ is preferably an optionallysubstituted C₃₋₁₀cycloaliphatic, C₂₋₁₀heterocycloaliphatic,C₆₋₁₂aromatic or C₁₋₉heteroaromatic group as herein generally andparticularly described. Most preferably R¹ is an optionally substitutedcycloaliphatic, especially C₃₋₇cycloalkyl group or an optionallysubstituted C₆₋₁₂aromatic, especially phenyl group as just described.

Particularly preferred Ar aromatic groups include optionally substitutedphenyl groups. Particularly preferred heteroaromatic groups includeoptionally substituted monocyclic heteroaromatic groups, especiallyoptionally substituted five- or six-membered heteroaromatic groupscontaining one, two, three or four heteroatoms selected from oxygen,sulphur or nitrogen atoms. Particularly preferred optionally substitutedmonocyclic heteroaromatic groups include optionally substituted furyl,thienyl, pyrrolyl, oxazolyl, thiazolyl, pyridyl, pyrimidinyl ortriazinyl group.

Particularly preferred optional substituents which may be present on Araromatic or heteroaromatic groups include those —R^(18a) or-L⁵Alk⁵(R^(18a))_(g) atoms or groups as hereinbefore defined in relationto preferred R¹ aromatic groups.

In general in compounds of the invention Ar is preferably an optionallysubstituted phenyl group as generally and specifically described hereinand in particular is a phenyl group.

In another preferred class of compounds of formula (1) and (2) m iszero.

In a further preferred class of compounds of formula (1) or (2) m is theinteger 1. In this class of compounds R^(c) is preferably an oxo (═O)atom or a C₁₋₆alkyl, most especially C₁₋₄alkyl e.g. methyl, ethyl ori-propyl group, or a haloC₁₋₆alkyl, most especially fluoroC₁₋₃alkyl e.g.—CHF₂ or —CF₃ group or a C₁₋₆alkoxy, especially C₁₋₃alkoxy e.g. methoxyor ethoxy or a haloC₁₋₆alkoxy, especially fluoroC₁₋₃alkoxy e.g.trifluoromethoxy group or a group -(Alk²)_(r)R⁵ in which R⁵ is a cyano,—CO₂R², especially —CO₂CH₃ or —CO₂C(CH₃)₃, —NHR² especially —NHCH₃,—N(R²)(R³) especially —N(CH₃)₂, —COR² especially —COCH₃ or —COCH₂CH₃,—N(R³)COR⁴, especially —NHCOR⁴ e.g. —NHCOCH3 or optionally substitutedC₃₋₇cycloalkyl, C₂₋₇heterocycloalkyl, C₆₋₁₂aromatic orC₁₋₉heteroaromatic group. In one preferred group of compounds of thisclass r is zero. In another preferred group of compounds of this class ris the integer 1 and Alk² is a C₁₋₃alkylene chain such as a —CH₂—,—CH₂CH₂—, —CH₂CH₂CH₂—, —CH(CH₃)CH₂— or —CH₂CH(CH₃)— chain.

Particularly preferred optionally substituted C₃₋₇cycloalkyl,C₂₋₇heterocycloalkyl, C₆₋₁₂aromatic or C₁₋₉heteroaromatic groupsrepresented by R⁵ include those preferred groups as described herein inrelation to R¹.

Particularly useful compounds according to the invention include thosedescribed in the Examples hereinafter and the salts, solvates, hydratesand N-oxides thereof.

Compounds according to the invention are potent and selective inhibitorsof p38 kinases, including all isoforms and splice variants thereof. Morespecifically the compounds of the invention are inhibitors of p38α, p38βand p38β2. The ability of the compounds to act in this way may be simplydetermined by employing tests such as those described in the Exampleshereinafter.

The compounds of formula (1) are of use in modulating the activity ofp38 kinases and in particular are of use in the prophylaxis andtreatment of any p38 kinase mediated diseases or disorders in a human,or other mammal. The invention extends to such a use and to the use ofthe compounds for the manufacture of a medicament for treating suchdiseases or disorders. Further the invention extends to theadministration to a human an effective amount of a p38 inhibitor fortreating any such disease or disorder.

The invention also extends to the prophylaxis or treatment of anydisease or disorder in which p38 kinase plays a role includingconditions caused by excessive or unregulated pro-inflammatory cytokineproduction including for example excessive or unregulated TNF, IL-1,IL-6 and IL-8 production in a human, or other mammal. The inventionextends to such a use and to the use of the compounds for themanufacture of a medicament for treating such cytokine-mediated diseasesor disorders. Further the invention extends to the administration to ahuman an effective amount of a p38 inhibitor for treating any suchdisease or disorder.

Diseases or disorders in which p38 kinase plays a role either directlyor via pro-inflammatory cytokines including the cytokines TNF, IL-1,IL-6 and IL-8 include without limitation autoimmune diseases,inflammatory diseases, destructive-bone disorders, proliferativedisorders, neurodegenerative disorders, viral diseases, allergies,infectious diseases, heart attacks, angiogenic disorders,reperfusion/ischemia in stroke, vascular hyperplasia, organ hypoxia,cardiac hypertrophy, thrombin-induced platelet aggregation andconditions associated with prostaglandin endoperoxidase synthetase-2(COX-2).

Autoimmune diseases which may be prevented or treated include but arenot limited to rheumatoid arthritis, inflammatory bowel disease,ulcerative colitis, Crohn's disease, multiple sclerosis, diabetes,glomerulonephritis, systemic lupus erythematosus, scleroderma, chronicthyroiditis, Grave's disease, hemolytic anemia, autoimmune gastritis,autoimmune neutropenia, thrombocytopenia, chronic active hepatitis,myasthenia gravis, atopic dermatitis, graft vs, host disease orpsoriasis.

The invention further extends to the particular autoimmune diseaserheumatoid arthritis.

Inflammatory diseases which may be prevented or treated include but arenot limited to asthma, allergies, respiratory distress syndrome or acuteor chronic pancreatitis.

Destructive bone disorders which may be prevented or treated include butare not limited to osteoporosis, osteoarthritis and multiplemyeloma-related bone disorder.

Proliferative diseases which may be prevented or treated include but arenot limited to acute or chronic myelogenous leukemia, Kaposi's sarcoma,metastic melanoma and multiple myeloma.

Neurodegenerative diseases which may be prevented or treated include butare not limited to Parkinson's disease, Alzheimer's disease, cerebralischemias or neurodegenerative disease caused by traumatic injury.

Viral diseases which may be prevented or treated include but are notlimited to acute hepatitis infection (including hepatitis A, hepatitis Band hepatitis C), HIV infection and CMV retinitis.

Infectious diseases which may be prevented or treated include but arenot limited to septic shock, sepsis and Shigellosis.

In addition, p38 inhibitors of this invention also exhibit inhibition ofexpression of inducible pro-inflammatory proteins such as prostaglandinendoperoxidase synthetase-2, otherwise known as cyclooxygenase-2 (COX-2)and are therefore of use in therapy. Pro-inflammatory mediators of thecyclooxygenase pathway derived from arachidonic acid are produced byinducible COX-2 enzyme. Regulation of COX-2 would regulate thesepro-inflammatory mediators such as prostaglandins, which affect a widevariety of cells and are important and critical inflammatory mediatorsof a wide variety of disease states and conditions. In particular theseinflammatory mediators have been implicated in pain, such as in thesensitization of pain receptors, or edema. Accordingly additional p38mediated conditions which may be prevented or treated include edema,analgesia, fever and pain such as neuromuscular pain, headache, dentalpain, arthritis pain and pain caused by cancer.

As a result of their p38 inhibitory activity, compounds of the inventionhave utility in the prevention and treatment of diseases associated withcytokine production including but not limited to those diseasesassociated with TNF, IL-1, IL-6 and IL-8 production.

Thus TNF mediated diseases or conditions include for example rheumatoidarthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis andother arthritic conditions, sepsis, septic shock syndrome, adultrespiratory distress syndrome, cerebral malaria, chronic pulmonaryinflammatory disease, silicosis, pulmonary sarcoiosis, bone resportiondisease, reperfusion injury, graft vs. host reaction, allograftrejections, fever and myalgias due to infection, cachexia secondary toinfection, AIDS, ARC or malignancy, keloid formation, scar tissueformation, Crohn's disease, ulcerative colitis, pyresis, viralinfections such as HIV, CMV, influenza and herpes; and vetinary viralinfections, such as lentivirus infections, including but not limited toequine infectious anemia virus, caprine arthritis virus, visna virus ormaedi virus; or retrovirus infections, including feline immunodeficiencyvirus, bovine immunodeficiency virus or canine immunodeficiency virus.

Compounds of the invention may also be used in the treatment of viralinfections, where such viruses elicit TNF production in vivo or aresensitive to upregulation by TNF. Such viruses include those thatproduce TNF as a result of infection and those that are sensitive toinhibition, for instance as a result of decreased replication, directlyor indirectly by the TNF inhibiting compounds of the invention. Suchviruses include, but are not limited to, HIV-1, HIV-2 and HIV-3,Cytomegalovirus (CMV), Influenza, adenovirus and the Herpes group ofviruses such as Herpes Zoster and Herpes Simplex.

IL-1 mediated diseases or conditions include for example rheumatoidarthritis, osteoarthritis, psoriatic arthritis, traumatic arthritis,rubella arthritis, inflammatory bowel disease, stroke, endotoxemiaand/or toxic shock syndrome, inflammatory reaction induced by endotoxin,diabetes, pancreatic β-cell disease, Alzheimer's disease, tuberculosis,atherosclerosis, muscle degeneration and cachexia.

IL-8 mediated diseases and conditions include for example thosecharacterized by massive neutrophil infiltration such as psoriasis,inflammatory bowel disease, asthma, cardiac, brain and renal reperfusioninjury, adult respiratory distress syndrome, thrombosis andglomerulonephritis. The increased IL-8 production associated with eachof these diseases is responsible for the chemotaxis of neutrophils intoinflammatory sites. This is due to the unique property of IL-8 (incomparison to TNF, IL-1 and IL-6) of promoting neutrophil chemotaxis andactivation. Therefore, inhibition of IL-8 production would lead to adirect reduction in neutrophil infiltration.

It is also known that both IL-6 and IL-8 are produced during rhinovirus(HRV) infections and contribute to the pathogenesis of the common coldand exacerbation of asthma associated with HRV infection [Turner et al,Clin. Infec. Dis., 1997, 26, 840; Grunberg et al, Am. J. Crit. Care Med.1997, 155, 1362; Zhu et al, J. Clin. Invest. 1996, 97, 421]. It has alsobeen demonstrated in vitro that infection of pulmonary epithelial cells(which represent the primary site of infection by HRV) with HRV resultsin production of IL-6 and IL-8 [Sabauste et al, J. Clin. Invest. 1995,96, 549]. Therefore, p38 inhibitors of the invention may be used for thetreatment or prophylaxis of the common cold or respiratory viralinfection caused by human rhinovirus infection (HRV), otherenteroviruses, coronavirus, influenza virus, parainfluenza virus,respiratory syncytial virus or adenovirus infection.

For the prophylaxis or treatment of a p38 or pro-inflammatory cytokinemediated disease the compounds according to the invention may beadministered to a human or mammal as pharmaceutical compositions, andaccording to a further aspect of the invention we provide apharmaceutical composition which comprises a compound of formula (1)together with one or more pharmaceutically acceptable carriers,excipients or diluents.

Pharmaceutical compositions according to the invention may take a formsuitable for oral, buccal, parenteral, nasal, topical, ophthalmic orrectal administration, or a form suitable for administration byinhalation or insufflation.

For oral administration, the pharmaceutical compositions may take theform of, for example, tablets, lozenges or capsules prepared byconventional means with pharmaceutically acceptable excipients such asbinding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidoneor hydroxypropyl methylcellulose); fillers (e.g. lactose,microcrystalline cellulose or calcium hydrogen phosphate); lubricants(e.g. magnesium stearate, talc or silica); disintegrants (e.g. potatostarch or sodium glycollate); or wetting agents (e.g. sodium laurylsulphate). The tablets may be coated by methods well known in the art.Liquid preparations for oral administration may take the form of, forexample, solutions, syrups or suspensions, or they may be presented as adry product for constitution with water or other suitable vehicle beforeuse. Such liquid preparations may be prepared by conventional means withpharmaceutically acceptable additives such as suspending agents,emulsifying agents, non-aqueous vehicles and preservatives. Thepreparations may also contain buffer salts, flavouring, colouring andsweetening agents as appropriate.

Preparations for oral administration may be suitably formulated to givecontrolled release of the active compound.

For buccal administration the compositions may take the form of tabletsor lozenges formulated in conventional manner.

The compounds for formula (1) may be formulated for parenteraladministration by injection e.g. by bolus injection or infusion.Formulations for injection may be presented in unit dosage form, e.g. inglass ampoule or multi dose containers, e.g. glass vials. Thecompositions for injection may take such forms as suspensions, solutionsor emulsions in oily or aqueous vehicles, and may contain formulatoryagents such as suspending, stabilising, preserving and/or dispersingagents. Alternatively, the active ingredient may be in powder form forconstitution with a suitable vehicle, e.g. sterile pyrogen-free water,before use.

In addition to the formulations described above, the compounds offormula (1) may also be formulated as a depot preparation. Such longacting formulations may be administered by implantation or byintramuscular injection.

For nasal administration or administration by inhalation, the compoundsfor use according to the present invention are conveniently delivered inthe form of an aerosol spray presentation for pressurised packs or anebuliser, with the use of suitable propellant, e.g.dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas ormixture of gases.

The compositions may, if desired, be presented in a pack or dispenserdevice which may contain one or more unit dosage forms containing theactive ingredient. The pack or dispensing device may be accompanied byinstructions for administration.

For topical administration the compounds for use according to thepresent invention may be conveniently formulated in a suitable ointmentcontaining the active component suspended or dissolved in one or morepharmaceutically acceptable carriers. Particular carriers include, forexample, mineral oil, liquid petroleum, propylene glycol,polyoxyethylene, polyoxypropylene, emulsifying wax and water.Alternatively the compounds for use according to the present inventionmay be formulated in a suitable lotion containing the active componentsuspended or dissolved in one or more pharmaceutically acceptablecarriers. Particular carriers include, for example mineral oil, sorbitanmonostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, benzylalcohol, 2-octyldodecanol and water.

For ophthalmic administration the compounds for use according to thepresent invention may be conveniently formulated as microionizedsuspensions in isotonic, pH adjusted sterile saline, either with orwithout a preservative such as bactericidal or fungicidal agent, forexample phenylmercuric nitrate, benzylalkonium chloride or chlorhexidineacetate. Alternatively for ophthalmic administration compounds may beformulated in an ointment such as petrolatum.

For rectal administration the compounds for use according to the presentinvention may be conveniently formulated as suppositories. These can beprepared by mixing the active component with a suitable non-irritatingexcipient which is solid at room temperature but liquid at rectaltemperature and so will melt in the rectum to release the activecomponent. Such materials include for example cocoa butter, beeswax andpolyethylene glycols.

The quantity of a compound of the invention required for the prophylaxisor treatment of a particular condition will vary depending on thecompound chosen, and the condition of the patient to be treated. Ingeneral, however, daily dosages may range from around 100 ng/kg to 100mg/kg e.g. around 0.01 mg/kg to 40 mg/kg body weight for oral or buccaladministration, from around 10 ng/kg to 50 mg/kg body weight forparenteral administration and around 0.05 mg to around 1000 mg e.g.around 0.5 mg to around 1000 mg for nasal administration oradministration by inhalation or insufflation.

The compounds of the invention may be prepared by a number of processesas generally described below and more specifically in the Exampleshereinafter. In the following process description, the symbols Ar, R¹,Alk¹, p, L¹, R^(a), R^(b), R^(c), R^(d), m, q, X and Y when used in theformulae depicted are to be understood to represent those groupsdescribed above in relation to formula (1) unless otherwise indicated.In the reactions described below, it may be necessary to protectreactive functional groups, for example hydroxy, amino, thio or carboxygroups, where these are desired in the final product, to avoid theirunwanted participation in the reactions. Conventional protecting groupsmay be used in accordance with standard practice [see, for example,Green, T. W. in “Protective Groups in Organic Synthesis”, John Wiley andSons, 1999]. In some instances, deprotection may be the final step inthe synthesis of a compound of formula (1) and the processes accordingto the invention described hereinafter are to be understood to extend tosuch removal of protecting groups. For convenience the processesdescribed below all refer to a preparation of a compound of formula (1)but clearly the description applies equally to the preparation ofcompounds of formula (2).

Thus according to a further aspect of the invention a compound offormula (1) in which R^(a) and R^(b) are joined to form an oxo (═O)group, X is a nitrogen atom and Y is an optionally substituted —NH—group [formula (1a)]may be prepared according to the reactions set outin Scheme 1.

Thus a compound of formula (1a) may be prepared by reaction of acompound of formula (3) [where Hal¹ is a halogen atom e.g. a chlorineatom) with a nucleophilic agent of formula R¹(Alk¹)_(p)L¹H, where -L¹His for example an —OH, —SH or —N(R¹⁰)H group.

The reaction may be performed in the presence of a solvent, for examplean ether such as an alcohol, e.g. 2-ethoxyethanol cyclic ether, e.g.tetrahydrofuran or dioxane, an aromatic hydrocarbon such as toluene or asubstituted amide such as dimethylformamide, optionally in the presenceof a base, for example an inorganic base such as sodium hydride, or anorganic base such as an organic amine, e.g. a cyclic amine such as1,5-diazabicyclo[4.3.0]non-5-ene or a resin bound organic amine such asresin bound2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine(PS-BEMP), at an elevated temperature, for example about 80° C. to thereflux temperature.

In a further aspect of the invention a compound of formula (1a) inwhich, for example, L¹ is a covalent bond and n is zero may be preparedby the Suzuki reaction of an intermediate of formula (3) [in which Hal¹is a halogen atom such as a chlorine, bromine or iodine atom] with aboronic acid of formula R¹B(OH)₂. The reaction may be performed in anorganic solvent, for example an aromatic hydrocarbon such as toluene oran ether such as an acyclic ether e.g. 1,2-dimethoxyethane or a cyclicether e.g. tetrahydrofuran optionally in the presence of a base such asan aqueous carbonate e.g. sodium or potassium carbonate in the presenceof a metal catalyst such as a palladium complex e.g.tetrakis(triphenylphosphine)palladium (0), at an elevated temperaturee.g. around 80° C.

Intermediate halo e.g. chlorpyrimidines of formula (3) may be preparedfrom intermediate piperazinones of formula (4) by reaction with anoptionally substituted di-halopyrimidine e.g. dichloropyrimidine. Thereaction may be performed using similar conditions to those justdescribed for the preparation of compounds of formula (1a) bynucleophilic displacement.

Piperazinones of formula (4) may be prepared from α-haloacetates offormula (5) [where Hal is a halogen atom such as a chlorine, bromine oriodine atom and R³⁰ is a C₁₋₆alkyl group such as a methyl] by reactionwith an optionally substituted diethylamine of formula:

The reaction may be performed in the presence of a solvent such as asubstituted amide for example dimethylformamide or an ether e.g. acyclic ether such as tetrahydrofuran or an alcohol such as methanol orethanol in the presence of a base, for example an inorganic base such asa hydride e.g. sodium hydride or an organic base such as1,5-diazabicyclo[4.3.0]non-5-ene or a trialkylamine such astriethylamine or a sodium alkoxide such as sodium methoxide or sodiumethoxide at a temperature between about ambient and the refluxtemperature.

According to another aspect of the invention further compounds offormula (1) may be prepared according to the methods set out in Scheme2. Thus a compound of formula (1b) in which R^(a) and R^(b) is each ahydrogen atom may be prepared from an intermediate of formula (6) by themethods previously described to form compounds of formula (1a).

Intermediates of formula (6) may be prepared from intermediates offormula (7) by the methods described to prepare intermediates of formula(3), optionally with the addition of a prior N-protection (e.g. BOCprotection) step and a subsequent N-deprotection step [in the case whereY is —NH—] under such standard conditions as described in Green (ibid).

Intermediates of formula (7) may be prepared from optionally substitutedintermediates of formula (8) [in which Hal² is a halogen atom such as abromine or iodine atom] by a two-step process involving reaction of anintermediate of formula (8) with a boronic acid of formula ArB(OH)₂under the Suzuki reaction conditions previously described and subsequentreduction of the pyrazine ring by catalytic hydrogenation. The reductionreaction may be performed in a solvent such as an alcohol, e.g. methanolor ethanol in the presence of a catalyst such as a palladium catalyste.g. palladium on charcoal in the presence of a source of hydrogen,preferably at an elevated pressure and optionally in the presence of anacid e.g. 6M hydrochloric acid and/or at an elevated temperature.

Further compounds of the invention in which R^(a) and R^(b) is each ahydrogen atom may be prepared from compounds of formula (1a) or fromintermediates of formula (9):

by reduction of the carbonyl group with an inorganic reducing agent suchas a hydride e.g. lithium aluminium hydride or a borane such asborane-methyl sulfide complex in a solvent such as an ether e.g. acyclic ether such as tetrahydrofuran or a halogenated hydrocarbon suchas dichloromethane at a temperature between about 0° C. and the refluxtemperature.

Further intermediates to compounds of the invention may be prepared bythe methods depicted in Scheme 3.

Intermediates of formula (12) may be prepared from intermediates offormula (10) by reaction with an intermediate of formula (11) in which Wis a halogen atom such as a chlorine, bromine or iodine atom by suchwell known metal catalysed coupling reactions as those of Buchwald (J.Am. Chem. Soc. 1996, 118, 7215-6; Tetrahedron Lett. 1997, 6359-62; J.Am. Chem. Soc. 1997, 199, 6054-58; J. Org. Chem. 1997, 62, 6066-8) orHartwig (J. Am. Chem. Soc. 1996, 118, 7217-8; J. Org. Chem. 1997, 62,1268-73).

Further intermediates (14) to compounds of the invention may be preparedfrom amino-alcohols [Y═O] or amino-thiols [Y═S] of formula (13) by themethod of Scheme 4.

The reaction may be performed in a solvent such as an amide e.g.dimethylformamide or an ether such as a cyclic ether e.g.tetrahydrofuran in the presence of a base, for example an inorganic basesuch as a carbonate e.g. potassium or caesium carbonate or a hydridee.g. sodium hydride or an organic base such as1,5-diazabicyclo[4.3.0]non-5-ene or a trialkylamine e.g. triethylamineor a sodium alkoxide such as sodium methoxide or sodium ethoxide at atemperature between about ambient and the reflux temperature.

Where in the general processes described above intermediates such asintermediates of formula (5), (8) and HL¹(Alk¹)_(p)R¹ and any otherintermediates required in the synthesis of compounds of the inventionare not available commercially or known in the literature, they may bereadily obtained from simpler known compounds by one or more standardsynthetic methods employing substitution, oxidation, reduction orcleavage reactions. Particular substitution approaches includeconventional alkylation, arylation, heteroarylation, acylation,thioacylation, halogenation, sulphonylation, nitration, formylation andcoupling procedures. It will be appreciated that these methods may alsobe used to obtain or modify other intermediates and in particularcompounds of formula (1) where appropriate functional groups exist inthese compounds. Particular examples of such methods are given in theExamples hereinafter.

Thus for example aromatic halogen substituents in the compounds may besubjected to halogen-metal exchange with a base, for example a lithiumbase such as n-butyl or t-butyl lithium, optionally at a lowtemperature, e.g. around −78° C., in a solvent such as tetrahydrofuranand then quenched with an electrophile to introduce a desiredsubstituent. Thus, for example, a formyl group may be introduced byusing dimethylformamide as the electrophile, a thiomethyl group may beintroduced by using dimethyidisulphide as the electrophile, an alcoholgroup may be introduced by using an aldehyde as electrophile and an acidmay be introduced by using carbon dioxide as electrophile. Aromaticacids of formula ArCO₂H may also be generated by quenching Grignardreagents of formula ArMgHal with carbon dioxide.

Aromatic acids of formula ArCO₂H generated by this method and acidcontaining compounds in general may be converted to activatedderivatives, e.g. acid halides by reaction with a halogenating agentsuch as a thionyl halide e.g. thionyl chloride, a phosphorous trihalidesuch as phosphorous trichloride or a phosphorous pentahalide such asphosphorous pentachloride optionally in an inert solvent such as anaromatic hydrocarbon e.g. toluene or a chlorinated hydrocarbon e.g.dichloromethane at a temperature from about 0° C. to the refluxtemperature, or may be converted into Weinreb amides of formulaArC(O)N(OMe)Me by conversion to the acid halide as just described andsubsequent reaction with an amine of formula HN(OMe)Me or a saltthereof, optionally in the presence of a base such as an organic amine,e.g. triethylamine in an inert solvent such as an aromatic hydrocarbone.g. toluene or a chlorinated hydrocarbon e.g. dichloromethane at atemperature from about 0° C. to ambient temperature.

Compounds of the invention and intermediates thereto such as compoundsof formulae (1a), (1b), (3), (6), (7), (13) and (14) may be prepared byalkylation, arylation or heteroarylation. For example, compoundscontaining a -L¹H or -L⁵H group (where L¹ or L⁵ is a linker atom orgroup) may be treated with an alkylating agent R¹(Alk¹)_(p)Z² or(R^(18a))_(g)Alk⁵Z² respectively in which Z² is a leaving atom or groupsuch as a halogen atom, e.g. a fluorine, chlorine, bromine or iodineatom or a sulphonyloxy group such as an alkylsulphonyloxy, e.g.trifluoromethylsulphonyloxy or arylsulphonyloxy, e.g.p-toluenesulphonyloxy group.

The reaction may be carried out in the presence of a base such as acarbonate, e.g. caesium or potassium carbonate, an alkoxide, e.g.potassium t-butoxide, or a hydride, e.g. sodium hydride, in a dipolaraprotic solvent such as an amide, e.g. a substituted amide such asdimethylformamide or an ether, e.g. a cyclic ether such astetrahydrofuran.

In another example, compounds containing a -L¹H or -L⁵H group as definedabove may be functionalised by acylation or thioacylation, for exampleby reaction with the alkylating agents just described but in which Z² isreplaced by a —C(O)Z³, C(S)Z³, —N(R²)COZ³ or —N(R²)C(S)Z³ group in whichZ³ is a leaving atom or group as described for Z². The reaction may beperformed in the presence of a base, such as a hydride, e.g. sodiumhydride or an amine, e.g. triethylamine or N-methylmorpholine, in asolvent such as a halogenated hydrocarbon, e.g. dichloromethane orcarbon tetrachloride or an amide, e.g. dimethylformamide, at for exampleambient temperature. Alternatively, the acylation may be carried outunder the same conditions with an acid (for example one of thealkylating agents described above in which Z² is replaced by a —CO₂Hgroup) in the presence of a condensing agent, for example a diimide suchas 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide orN,N′-dicyclohexylcarbodiimide, or a benzotriazole such as[O-(7-azabenzo-triazol-1-yl)-1,1,3,3-tetramethyluronium]hexafluorophosphateadvantageously in the presence of a catalyst such as a N-hydroxycompound e.g. a N-hydroxytriazole such as 1-hydroxybenzotriazole.Alternatively the acid may be reacted with a chloroformate, for exampleethylchloroformate, prior to the desired acylation reaction

In a further example compounds may be obtained by sulphonylation of acompound containing an —OH group by reaction with one of the abovealkylating agents but in which Z² is replaced by a —S(O)Hal or —SO₂Halgroup [in which Hal is a halogen atom such as chlorine atom] in thepresence of a base, for example an inorganic base such as sodium hydridein a solvent such as an amide, e.g. a substituted amide such asdimethylformamide at for example ambient temperature.

In another example, compounds containing a -L¹H or -L⁵H group as definedabove may be coupled with one of the alkylation agents just describedbut in which Z² is replaced by an —OH group in a solvent such astetrahydrofuran in the presence of a phosphine, e.g. triphenylphosphineand an activator such as diethyl, diisopropyl- ordimethylazodicarboxylate.

Ester groups such as —CO₂Alk⁶ and —CO₂R² in the compound of formula (1)and intermediates thereto may be converted to the corresponding acid[—CO₂H] by acid- or base-catalysed hydrolysis depending on the nature ofthe group Alk⁶ or R². Acid- or base-catalysed hydrolysis may be achievedfor example by treatment with an organic or inorganic acid, e.g.trifluoroacetic acid in an organic solvent e.g. dichloromethane or amineral acid such as hydrochloric acid in a solvent such as dioxan or analkali metal hydroxide, e.g. lithium hydroxide in an aqueous alcohol,e.g. aqueous methanol.

In a further example, —OR¹⁴ [where R¹⁴ represents a C₁₋₆alkyl group suchas methyl group] in compounds of formula (1) and intermediates theretomay be cleaved to the corresponding alcohol —OH by reaction with borontribromide in a solvent such as a halogenated hydrocarbon, e.g.dichloromethane at a low temperature, e.g. around —78° C.

Alcohol [—OH] groups may also be obtained by hydrogenation of acorresponding —OCH₂R³¹ group (where R³¹ is an aryl group) using a metalcatalyst, for example palladium on a support such as carbon in a solventsuch as ethanol in the presence of ammonium formate, cyclohexadiene orhydrogen, from around ambient to the reflux temperature. In anotherexample, —OH groups may be generated from the corresponding ester [e.g.—CO₂Alk⁶] or aldehyde [—CHO] by reduction, using for example a complexmetal hydride such as lithium aluminium hydride or sodium borohydride ina solvent such as methanol.

In another example, alcohol —OH groups in the compounds may be convertedto a corresponding —OR¹⁴ group by coupling with a reagent R¹⁴OH in asolvent such as tetrahydrofuran in the presence of a phosphine, e.g.triphenylphosphine and an activator such as diethyl-, diisopropyl-, ordimethylazodicarboxylate.

Aminosulphonylamino [—NHSO₂NH₂] groups in the compounds may be obtained,in another example, by reaction of a corresponding amine [—NH₂] withsulphamide in the presence of an organic base such as pyridine at anelevated temperature, e.g. the reflux temperature.

In another example compounds containing a —NHCSR⁶ or —CSNHR⁶ group orcompounds where R^(a) and R^(b) together form a thio (═S) group may beprepared by treating a corresponding compound containing a —NHCOR⁶ or—CONHR⁶ or R^(a)-R^(b) oxo (═O) group with a thiation reagent, such asLawesson's Reagent or P₂S₅, in an anhydrous solvent, for example acyclic ether such as tetrahydrofuran, at an elevated temperature such asthe reflux temperature.

In a further example amine (—NH₂) groups may be alkylated using areductive alkylation process employing an aldehyde and a reducing agent.Suitable reducing agents include borohydrides for example sodiumtriacetoxyborohyride or sodium cyanoborohydride. The reduction may becarried out in a solvent such as a halogenated hydrocarbon, e.g.dichloromethane, a ketone such as acetone, or an alcohol, e.g. ethanol,where necessary in the presence of an acid such as acetic acid at aroundambient temperature. Alternatively, the amine and aldehyde may beinitially reacted in a solvent such as an aromatic hydrocarbon e.g.toluene and then subjected to hydrogenation in the presence of a metalcatalyst, for example palladium on a support such as carbon, in asolvent such as an alcohol, e.g. ethanol.

In a further example, amine [—NH₂] groups in compounds of formula (1)and intermediates thereto may be obtained by hydrolysis from acorresponding imide by reaction with hydrazine in a solvent such as analcohol, e.g. ethanol at ambient temperature.

In another example, a nitro [—NO₂] group may be reduced to an amine[—NH₂], for example by catalytic hydrogenation using for examplehydrogen in the presence of a metal catalyst, for example palladium on asupport such as carbon in a solvent such as an ether, e.g.tetrahydrofuran or an alcohol e.g. methanol, or by chemical reductionusing for example a metal, e.g. tin or iron, in the presence of an acidsuch as hydrochloric acid.

In a further example amine (—CH₂NH₂) groups in compounds of formula (1)and intermediates thereto may be obtained by reduction of nitriles(—CN), for example by catalytic hydrogenation using for example hydrogenin the presence of a metal catalyst, for example palladium on a supportsuch as carbon, or Raney® nickel, in a solvent such as an ether e.g. acyclic ether such as tetrahydrofuran or an alcohol e.g. methanol orethanol, optionally in the presence of ammonia solution at a temperaturefrom ambient to the reflux temperature, or by chemical reduction usingfor example a metal hydride e.g. lithium aluminium hydride, in a solventsuch as an ether e.g. a cyclic ether such as tetrahydrofuran, at atemperature from 0° C. to the reflux temperature.

In another example, sulphur atoms in the compounds, for example whenpresent as a Y atom or in a group L¹ or L² may be oxidised to thecorresponding sulphoxide or sulphone using an oxidising agent such as aperoxy acid, e.g. 3-chloroperoxybenzoic acid, in an inert solvent suchas a halogenated hydrocarbon, e.g. dichloromethane, at around ambienttemperature.

In a further example N-oxides of compounds of formula (1) may in generalbe prepared for example by oxidation of the corresponding nitrogen baseusing an oxidising agent such as hydrogen peroxide in the presence of anacid such as acetic acid, at an elevated temperature, for example around70° C. to 80° C., or alternatively by reaction with a peracid such asperacetic acid or m-chloroperoxybenzoic acid in a solvent,such as ahalogenated hydrocarbon e.g. dichloromethane or an alcohol e.g.tert-butanol at a temperature from the ambient temperature to the refluxtemperature.

In another example further compounds of the invention using such wellknow and commonly used reactions as are to be found in the generalreference texts Rodd's Chemistry of Carbon Compounds, Volumes 1-15 andSupplementals (Elsevier Science Publishers, 1989), Fieser and Fieser'sReagents for Organic Synthesis, Volumes 1-19 (John Wiley and Sons,1999), Comprehensive Heterocyclic Chemistry, Ed. Katritzky et al,Volumes 1-8, 1984 and Volumes 1-11, 1994 (Pergamon), ComprehensiveOrganic Functional Group Transformations, Ed. Katritzky et al, Volumes1-7, 1995 (Pergamon), Comprehensive Organic Synthesis, Ed. Trost andFlemming, Volumes 1-9, (Pergamon, 1991), Encyclopedia of Reagents forOrganic Synthesis, Ed. Paquette, Volumes 1-8 (John Wiley and Sons,1995), Larock's Comprehensive Organic Transformations (VCH PublishersInc., 1989) and March's Advanced Organic Chemistry (John Wiley and Sons,5^(th) Ed., 2001).

Salts of compounds of formula (1) may be prepared by reaction ofcompounds of formula (1) with an appropriate base in a suitable solventor mixture of solvents e.g. an organic solvent such as an ether e.g.diethylether, or an alcohol, e.g. ethanol using conventional procedures.

Where it is desired to obtain a particular enantiomer of a compound offormula (1) this may be produced from a corresponding mixture ofenantiomers using any suitable conventional procedure for resolvingenantiomers.

Thus for example diastereomeric derivatives, e.g. salts, may be producedby reaction of a mixture of enantiomers of formula (1) e.g. a racemate,and an appropriate chiral compound, e.g. a chiral base. Thediastereomers may then be separated by any convenient means, for exampleby crystallisation and the desired enantiomer recovered, e.g. bytreatment with an acid in the instance where the diastereomer is a salt.

In another resolution process a racemate of formula (1) or may beseparated using chiral High Performance Liquid Chromatography.Alternatively, if desired a particular enantiomer may be obtained byusing an appropriate chiral intermediate in one of the processesdescribed above. Alternatively, a particular enantiomer may be obtainedby performing an enantiomer specific enzymatic biotransformation e.g. anester hydrolysis using an esterase and then purifying only theenantiomerically pure hydrolysed acid from the unreacted ester antipode.

Chromatography, recrystallisation and other conventional separationprocedures may also be used with intermediates or final products whereit is desired to obtain a particular geometric isomer of the invention.

The following Examples illustrate the invention. All temperatures are in° C. The following abbreviations are used:

-   -   NMM—N-methylmorpholine; EtOAc—ethyl acetate;    -   MeOH—methanol; BOC—butoxycarbonyl;    -   DCM—dichloromethane; AcOH—acetic acid;    -   DIPEA—diisopropylethylamine; EtOH—ethanol;    -   Pyr—pyridine; Ar—aryl;    -   DMSO—dimethylsulphoxide; iPr—isopropyl;    -   Et₂O—diethylether; Me—methyl;    -   THF—tetrahydrofuran, DMF—N,N-dimethylformamide;    -   FMOC—9-fluorenylmethoxycarbonyl; NBS—N-bromosuccinimide    -   DBU—1,8-Diazabicyclo[5,4-0]undec-7-ene    -   MCPBA—3-chloroperoxybenzoic acid    -   PS-BEMP—resin bound        2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine

All NMR's were obtained either at 300 MHz or 400 MHz.

Compounds were named with the aid of Beilstein Autonom supplied by MDLInformation Systems GmbH, Theodor-Heuss-Allee 108, D60486 Frankfurt,Germany, or were given names that appear consistent with this.

Experimental

LCMS retention times (RT) quoted were generated on a Hewlett Packard1100 LC/MS using the following method: Phenomenex Luna 3 μC₁₈(2) 50×4.6mm column; mobile phase A=0.1% formic acid in water; mobile phase B=0.1%formic acid in MeCN; flow rate of 0.9 mLmin⁻¹, column temperature 40° C.Gradient:- Time % B Initial 5 2.00 95 3.00 95 5.0  5 5.5  endIntermediate 1

3-Phenyl-piperazin-2-one

Methyl bromophenyl acetate (25 g, 109 mmol) and ethylene diamine (13.1g, 218 mmol) were mixed in dry MeOH (180 mL) and stirred at roomtemperature for 15 minutes under nitrogen. Sodium methoxide (6.5 g, 120mmol) was added in one portion and the mixture heated to reflux for 3.5hr. The mixture was left stirring overnight at room temperature. Thesolvent was evaporated in vacuo to give a pale yellow gum, which waspartitioned between water (100 mL) and chloroform (100 mL), the pH ofthe aqueous phase was adjusted with 2M HCl to pH 7.5 and extracted withmore chloroform (100 mL). The combined organic phases were dried (MgSO₄)and evaporated to give the title compound as a pale yellow solid (17 g,89%).

δH NMR (CDCl₃): 7.42-7.15 (5H, m), 6.85 (1H, br-s), 4.5 (1H, s),3.52-3.20 (2H, m), 3.00 (2H, m), 2.50 (1 H, br-s).

LCMS (ES⁺) Retention time 0.65 minutes, 177 (MH)⁺.

Intermediate 2

4-(2-Chloro-pyrimidin-4-yl)-3-phenyl-piperazln-2-one

Intermediate 1, (0.5 g, 2.84 mmol), 2,4-dichloropyrimidine (0.47 g, 3.13mmol) and sodium bicarbonate (0.26 g, 3.13 mmol) in dry EtOH (5 mL) wererefluxed for 30 minutes under an atmosphere of nitrogen. The mixture wasfiltered, and the filtrate evaporated in vacuo to give a yellow solid asa 4:1 mixture of regioisomers in favour of the required isomer. Thesolid was purified by flash chromatography (1% MeOH in DCM followed by10% MeOH in DCM/silica) to give the required isomer as a pure whitesolid.

δH NMR (d₆ DMSO): 8.45 (1H, br-s), 8.25 (1H, d, J=6.0 Hz), 7.5-7.2 (5H,m), 6.76 (1 H, br-s), 5.82 (1 H, br-s), 4.0-3.2 (4H, m).

LCMS (ES⁺) Retention time 2.72 minutes, 289 (MH)⁺.

Intermediate 3

4-(2-Chloro-pyrimidin-4-yl)-1-methyl-3-phenyl-piperazin-2-one

To a solution of Intermediate 2, (0.20 g, 0.69 mmol) in dry toluene (10mL) was added PS-BEMP (0.5 g) and methyl iodide (0.29 g, 2.08 mmol) inone portion, under an atmosphere of nitrogen. The mixture was heatedunder reflux for 18 hrs. The brown suspension was filtered and thefiltrate evaporated in vacuo to give a yellow oil. The oil was purifiedby chromatography (0-5% MeOH in EtOAc/silica) to give the title compoundas a white solid (0.15 g, 72%).

LCMS (ES⁺) Retention time 3.05 minutes, 303 (MH)⁺.

Intermediate 4

4-(2-Chloro-pyrimidin-4-yl)-1-cyclopropylmethyl-3-phenyl-piperazin-2-one

To a solution of Intermediate 2, (0.20 g, 0.69 mmol) in dry toluene (10mL) was added PS-BEMP (0.5 g) and cyclopropylmethyl bromide (0.28 g,2.07 mmol) in one portion, under an atmosphere of nitrogen. The mixturewas heated under reflux for 48 hrs. The brown suspension was filteredand the filtrate evaporated in vacuo to give a yellow oil. The oil waspurified by chromatography (0-5% MeOH in EtOAc/silica) to give the titlecompound as a white solid (0.16 g, 67%).

LCMS (ES⁺) Retention time 3.36 minutes, 343 (MH)⁺.

Intermediate 5

1-Benzyl-4-(2-chloro-pyrimidin-4-yl)-1-methyl-3-phenyl-piperazin-2-one

Intermediate 2, (0.30 g, 1.04 mmol) and benzyl bromide (0.54 g, 3.11mmol) were reacted together following the procedure detailed forIntermediate 3, which gave the title compound as a pale yellow solid(0.39 g, 99%). Taken to the next step without purification (>90%).

LCMS (ES⁺) Retention time 3.61 minutes, 379 (MH)⁺.

Intermediate 6

1-Allyl-4(2-chloro-pyrimidinyl-4-yl)-3-phenyl-piperazin-2-one

Intermediate 2, (0.30 g, 1.04 mmol) and allyl bromide (0.38 g, 3.11mmol) were reacted together following the procedure detailed forIntermediate 3, which gave the title compound as a yellow solid (0.27 g,78%). This was taken to the next step without any purification(crude>90%).

δH NMR (d₃ MeOD): 7.95 (1H, d, J=6.15 Hz), 7.47-7.21 (5H, m), 6.55 (1H,d, J=6.2 Hz), 5.95 (1H, br-s), 5.66 (1H, m), 5.07 (2H, m), 4.00-3.86(4H, m), 3.42 (2H, m).

LCMS (ES⁺) Retention time 3.31 minutes, 329 (MH)⁺.

Intermediate 7

Bromo-(4-fluoro-phenyl)-acetic acid methyl ester

4-Fluorophenylacetic acid methyl ester (3.0 g, 17.6 mmol) in THF (20 mL)under nitrogen at −78° was treated with 1M lithium hexamethyldisilazide(19.4 mL, 19.4 mmol) and stirred at −78° for fifteen minutes. Trimethylsilyl chloride was added (2.23 mL, 17.6 mmol) and the reaction stirredfor a further fifteen minutes. Bromine (0.9 mL, 17.6 mmol) was added andthe reaction stirred again for a further fifteen minutes then quenchedwith water and partitioned between DCM and sodium hydrogen carbonatesolution. The organic phase was separated, dried (sodium sulphate) andconcentrated in vacuo. Flash chromatography (diethylether-silica)yielded the title compound.

δH NMR (CDCl₃): 7.42-7.35 (2H, m), 6.94-6.85 (2H, m), 5.18 (1H, s), 3.64(3H, s).

Intermediate 8

3-(4-Fluoro-phenyl)-piperazin-2-one

Intermediate 7, (4.0 g, 16.2 mmol) and ethylene diamine (2.2 mL, 33mmol) were mixed and stirred at room temperature for ten minutes inmethanol. Sodium methoxide (0.97 g, 18.0 mmol) was added as a solid andthe reactions heated under reflux for three hours. Concentratedhydrochloric acid was added to neutralise the excess sodium methoxideand the reaction mixture concentrated in vacuo. Chromatography (ethylacetate-tetrahydrofuran 0-100%—silica) yielded the title compound.

δH NMR (CDCl₃): 7.45-7.34 (2H, m), 7.08-7.01 (2H, m), 6.62 (1H, br-s),4.56 (1H, s), 3.59-3.48 (1 H, m), 3.41-3.31 (1H, m), 3.21-3.05 (2H, m).

Intermediate 9

4-(2-Chloro-pyrimidin-4-yl)-3-(4-fluoro-phenyl)-piperazin-2-one

Intermediate 8, (4.8 g, 24.7 mmol) and 2,4-dichloropyrimidine (3.6 g,24.2 mmol) in ethoxyethanol (40 mL) were heated at 100° for four hours.The reaction mixture was concentrated in vacuo and the residuechromatographed (DCM-50% THF/DCM-silica) to yield the title compound.

δH NMR (CDCl₃): 8.11 (1H, d, J=6.07 Hz), 7.45-7.41 (2H, m), 7.11-7.05(2H, m), 6.55 (1H, br-s), 6.30 (1H, d J=6.07 Hz), 5.76 (1H, br-s),4.28-4.23 (1H, m), 3.85-3.77 (1H, m), 3.62-3.43 (2H, m).

LCMS (ES⁺) Retention time 2.865 minutes, 307 (MH)⁺

Intermediate 10

2-Phenyl-piperazine

Intermediate 1 (7.7 g, 43.8 mmol), was added as a solid to lithiumaluminium hydride (7.5 g, 198 mmol) in THF (250 mL) under nitrogen andstirred at room temperature for three hours. After quenching with 2Msodium hydroxide the precipitate was filtered off and the solid residuewashed with THF. The combined organic filtrates were concentrated invacuo to yield the title compound 7 g).

δH NMR (d₆ DMSO): 7.37-7.34 (2H, m), 7.31-7.27 (2H, m), 7.24-7.19 (2H,m), 3.61-3.57 (1H, m), 2.92-2.84 (1H, m), 2.82-2.66 (3H, m), 2.63-2.55(1H, m), 2.41-2.33 (1H, m).

Intermediate 11

3-Phenyl-piperazine-1-carboxylic acid tert-butyl ester

Intermediate 10, (7 g, 43.2 mmol) in DCM (20 mL) and toluene (150 mL)was treated with carbonic acid di-tert-butyl ester (8.5 g, 38.9 mmol)and stirred for thirty minutes at room temperature then heated to 80°for two hours. The reaction mixture was concentrated in vacuo and theresidue chromatographed (DCM/5% MeOH/0.5% triethylamine-silica), toyield the title compound (4.1 g).

δH NMR (CDCl₃): 7.36-7.31 (2H, m), 7.30-7.20 (3H, m), 4.08-3.88 (2H,br-m), 3.68-3.60 (1H, m), 3.03-2.97 (1H, m), 2.92-2.78 (2H, m),2.76-2.61 (1H, br-m), m), 1.74-1.56 (1H, br-m), 1.40 (9H, s).

Intermediate 12

4-(2-Chloro-pyrimidin-4-yl)-3-phenyl-piperazine-1-carboxylic acidtert-butyl ester

Intermediate 11, (0.5 g, 1.9 mmol) and 2,4-dichloropyrimidine (0.28 g,1.9 mmol) were dissolved in EtOH (5 mL) and treated with sodium hydrogencarbonate (0.18 g, 2.1 mmol), the reaction was heated under reflux forfour hours then left to stand at room temperature over night. Thereaction mixture was concentrated in vacuo and chromatographed(EtOAc/hexane-silica) to yield the title compound (437 mg).

δH NMR (d₃ MeOD): 7.88 (1H, d, J, 6.24 Hz), 7.28-7.24 (2H, m), 7.20-7.17(3H, m), 6.46 (1H, br-d, J=5.47), 5.38 (1H, br-s), 4.36-4.21 (2H, m),3.79-3.58 (1H, m), 3.56 (2H, m), 3.22-3.20 (1H, m), 1.29-1.23 (9H,br-s), amide conformers present.

LCMS (ES⁺) Retention time 3.857 minutes, 375(MH)⁺

Intermediate 13

4-[2-(3-Chloro-phenylamino)-pyrimidin-4-yl]-3-phenyl-piperazine-1-carboxylicacid tert-butyl ester

Intermediate 12, (500 mg, 1.34 mmol) and 3-chloroaniline (879 mg, 6.89mmol) were dissolved in ethoxyethanol (3 mL) and treated withtrifluoroacetic acid (314 mg, 2.75 mmol) and stirred at 90° for fourhours. The reaction mixture was cooled, diluted with EtOAc, washed withsaturated sodium hydrogen bicarbonate solution dried over sodiumsulphate and concentrated in vacuo. Chromatography (0-50%EtOAc-DCM-silica) yielded the title compound as mixtures of conformers.

δH NMR (d₆ DMSO): 8.95 (1H, s), 8.00 (1H, d, J=6.04 Hz), 7.86 (1H, t,J=2.02 Hz), 7.55-7.52 (1H, m), 7.36-7.16 (6H, m), 6.90-6.87 (1H, m),6.18 (1H, d, J=6.07 Hz), 5.54 (1H, t, J=3.81 Hz), 4.31-4.18 (2H, m),3.79-3.73 (1H, m), 3.64-3.57 (1H, m), 3.55-3.48 (1H, m), 3.29-3.22 (1H,m), 1.33 (9H, s).

LCMS (ES⁺) Retention time 2.953 minutes, 466(MH)⁺.

Intermediate 14

2-Phenylpyridine

2-Chloropyridine (10 g, 88.0 mmol), phenylboronic acid (12.9 g, 105.7mmol), tetrakis(triphenylphosphine)palladium (0) (5.0 g, 5 mol %) and 2MNa₂CO₃ (50 mL) were all dissolved in ethylene glycol dimethylether (200mL) at room temperature, under an atmosphere of nitrogen. The mixturewas refluxed for 48 hours. Ethylene glycol dimethylether was evaporatedin vacuo to give a red oil, which was partitioned between water (10 mL)and EtOAc (10 mL). The EtOAc layer was separated and the aqueous layerwas further extracted with EtOAc (10 mL×2). The combined EtOAc layerswere dried (MgSO₄) and concentrated in vacuo to a red oil. Purificationby flash column chromatography (iso-hexaneethyl acetate 1:5-silica) gavethe title product as a colourless oil (9.6 g, 70%).

δH (CDCl₃): 8.70 (1H, m) 7.95 (2H, m), 7.70 (2H, m), 7.5-7.1 (4H, m).

LCMS (ES⁺) Retention time 2.50 minutes, 156 (MH)⁺.

Intermediate 15

2-Phenylpiperidine

2-Phenylpyridine, Intermediate 14, (4.0 g, 25.81 mmol), and concentratedHCl (3 mL) in EtOH (15 mL) were treated with platinum oxide andsubjected to catalytic hydrogenation (˜1 atm, balloon), at roomtemperature for 72 hours. After removal of the catalyst by filtration,the solution was evaporated in vacuo to a pale yellow HCl salt of theproduct. The free base is obtained by treating the residue with 10%aqueous sodium hydroxide. The aqueous is then extracted with Et₂Oseveral times and the extracts dried (MgSO₄) and evaporated to an oil togive the title compound.

δH NMR (d₆ DMSO): 9.41 (1H, d), 7.40 (5H, m), 4.12 (2H, d), 3.0 (3H, m),1.83 (3H, m).

LCMS (ES⁺) Retention time 0.82 minutes, 162 (MH)⁺.

Intermediate 16

2-Chloro-4-(2-phenyl-piperidin-1-yl)-pyrimidine

2-Phenylpiperidine, Intermediate 15, (0.5 g, 2.52 mmol),2,4-dichloropyrimidine (0.41 g, 2.77 mmol) and sodium bicarbonate (0.59g, 5.55 mmol) in dry EtOH (10 mL) were refluxed for 2 hours, under anatmosphere of nitrogen. The mixture was filtered and the filtrateevaporated in vacuo to give a yellow oil. The oil was purified by flashchromatography (EtOAc and isohexane (1:3)/silica) to give the titlecompound as a colourless oil (46 g, 66%).

δH NMR (CDCl₃): 7.95 (1H, d, J=6.0 Hz), 7.30-7.00 (5H, m), 6.25 (1H, d,J=6.0 Hz), 5.50 (1H, br-s), 4.35 (1H, m), 3.00 (1H, m), 2.30 (1H, m),1.95 (1H, m), 1.60 (4H, m).

LCMS (ES⁺) Retention time 3.87 minutes, 275 (MH)⁺.

Intermediate 17

(R)-5-Phenyl-morpholin-3-one

(R)-Phenylglycinol (0.20 g, 1.46 mmol) in dry THF (10 mL) was treatedwith triethylamine (0.18 g, 1.75 mmol) in one portion at 0°, under anatmosphere of nitrogen. Chloroacetylchloride (0.20 g, 1.75 mmol) wasadded dropwise over 15 minutes at 0°. The mixture was allowed to reachroom temperature over 1 hour then quenched with water (5 mL) and EtOAc(5 mL). The organic layer was washed with brine (10 mL), dried (MgSO₄)and evaporated in vacuo to a white solid. NMR shows the precursor to theproduct (non ring closed). The solid was dissolved in dry THF (5 mL) and10M NaOH was added slowly at 0°. The suspension was allowed to reachroom temperature over 1.5 hours. The suspension was diluted with water(10 mL) and EtOAc (10 mL) and the organic layer was further washed withwater (10 mL), then dried (MgSO₄) and evaporated in vacuo to a crudeyellow solid, which was taken to the next step without any purification.

δH NMR (CDCl₃): 7.39-7.04 (5H, m), 4.60 (1H, m), 4.14 (2H, d, J=16.7Hz), 4.05 (2H, d, J=16.7 Hz), 4.00 (1H, dd, J=4.3 and 13.2 Hz), 3.46(1H, dd, J=8.0 and 11.8 Hz).

LCMS (ES⁺) Retention time 2.47 minutes, 177 (MH)⁺. (Data andexperimental are the same for the S-enantiomer).

Intermediate 18

(R)3-Phenyl-morpholine

Intermediate 17, (0.17 g, 0.96 mmol) in dry THF (10 mL) was treated withlithium aluminum hydride (0.17 g, wt/wt) in one portion at 0°, under anatmosphere of nitrogen. The mixture was allowed to reach roomtemperature and stirred at room temperature for 2 hours. The suspensionwas slowly quenched with saturated sodium bicarbonate (10 mL) at 0°, andthen filtered through Celite® and the filtrate evaporated in vacuo to ayellow oil. The oil was purified by flash column chromatography(EtOAc/silica) to give the title compound as a pale yellow oil (0.09 g,57%).

δH NMR (CDCl₃): 7.45-7.10 (5H, m), 3.80 (3H, m), 3.55 (1H, m), 3.37 (1H,m), 3.05 (1H, m), 2.90 (1H, m).

LCMS (ES⁺) Retention time 0.62 minutes, 164 (MH)⁺. (Data andexperimental are the same for the S-enantiomer).

Intermediate 19

(R)-4-(2-Chloro-pyrimidin-4-yl)-3-phenyl-morpholine

Intermediate 18, (1.0 g, 6.13 mmol) and 2,4-dichloropyrimidine (1.0 g,6.71 mmol) were reacted together following the procedure detailed forIntermediate 2, which gave the title compound as a white solid (0.72 g,43%).

δH NMR (CDCl₃): 7.97 (1H, d, J=6.1 Hz), 7.33-7.15 (5H, m), 6.27 (1H, d,J=6.1 Hz), 5.30 (1H, br-s), 4.35 (1H, d, J=12.0 Hz), 4.18-3.90 (3H, m),3.64 (1H, m), 3.35 (1H, m).

LCMS (ES⁺) Retention time 3.36 minutes, 276 (MH)⁺. (Data andexperimental are the same for the S-enantiomer).

Intermediate 20

4-(5-Bromo-2-chloro-pyrimidin-4-yl)-3-phenyl-piperazin-2-one

To a solution of Intermediate 1, (4.38 g, 24.9 mmol) in MeOH (200 mL)were added 5-bromo-2,4-dichloropyrimidine (5.15 g, 22.6 mmol) and sodiumbicarbonate (3.8 g, 45.2 mmol). The mixture was stirred at roomtemperature for 2 days. The reaction mixture was concentrated in vacuo.The residue was dissolved in 1% MeOH:DCM and washed with water andbrine, dried over magnesium sulphate and concentrated in vacuo. Theresidue was recrystallised from MeOH to give the title compound as awhite crystalline solid (4.95 g).

δH NMR (CDCl₃): 8.14 (1H, s), 7.38 (2H, m), 7.18 (3H, m), 6.47 (1H,br-s), 6.25 (1H, s), 4.38 (1H, m), 3.60 (1H, m), 3.37 (1H, m), 3.19 (1H,m).

Intermediate 21

3-Phenyl-4-[5-bromo-2-(1(R)-phenyl-ethylamino)-pyrimidin-4-yl]-piperazin-2-one

To a solution of Intermediate 20, (400 mg, 1.09 mmol) in ethoxyethanol(5 mL) was added (R)-(−)-α-methylbenzylamine (330 mg, 2.72 mmol). Themixture was stirred at 100° for 16 hr. The mixture was cooled andconcentrated in vacuo. The residue was dissolved in 1% MeOH:DCM andwashed with water and brine, dried over magnesium sulphate andconcentrated in vacuo. The residue was recrystallised from MeOH/acetoneto give the title compound as a white crystalline solid (261 mg).

LCMS (ES⁺) Retention time 3.116 minutes, 453 (MH)⁺.

EXAMPLE 13-Phenyl-4-[2-(3-trifluoromethyl-benzylamino)-pyrimidin-4-yl]-piperazin-2-one

Intermediate 2, (0.20 g, 0.69 mmol) in dry EtOH (10 mL) was added tosodium bicarbonate (0.38 g, 4.56 mmol) and 3-trifluoromethyl benzylamine(0.79 g, 4.56 mmol) in one portion at room temperature under anatmosphere of nitrogen. The suspension was refluxed for 48 hours, cooledthen filtered and the filtrate evaporated in vacuo to a yellow gum. Thegum was purified by chromatography (1-10% MeOH in EtOAc/silica) to givethe title compound as a white solid.

δH NMR (CDCl₃): 7.89 (1H, d, J=5.95 Hz),7.67-7.21 (9H, m), 5.96 (1H,br-s), 5.85 (1H, d, J=6.0 Hz), 4.64 (2H, m), 3.95 (1H, br-s), 3.70 (1H,m), 3.42 (2H, m).

LCMS (ES⁺) Retention time 2.42 minutes, 428 (MH)⁺.

EXAMPLE 23-[4-(4-Methyl-3-oxo-2-phenyl-piperazin-1-yl)-pyrimidin-2-ylamino]-benzonitrile

Intermediate 3, (0.15 g, 0.50 mmol) in dry ethoxyethanol (5 mL) wasadded to 3-cyanoamine (0.06 g, 0.54 mmol), under an atmosphere ofnitrogen. The mixture was heated to 100° and stirred for 18 hrs, thencooled and evaporated in vacuo to give a brown oil. The oil was purifiedby flash column chromatography (5-10% MeOH in EtOAc/silica) to give thetitle compound as a white solid (0.11 g, 58%).

δH NMR (d₃ MeOD): 7.90 (2H, m), 7.60 (1H, d, J=6.0 Hz), 7.45-7.09 (8H,m), 6.18 (1H, d, J=6.2 Hz), 6.09 (1H, br-s), 3.95 (1H, m), 3.72 (1H, m),3.54 (2H, m), 2.95 (3H, s).

LCMS (ES⁺) Retention time 4.05 minutes, 332 (MH)⁺.

EXAMPLE 33-[4-(4-Cyclopropylmethyl-3-oxo-2-phenyl-piperazin-1-yl)-pyrimidin-2-ylamino]-benzonitrile

Intermediate 4, (0.20 g, 0.58 mmol) and 3-cyanoaniline (0.14 g, 1.17mmol) were reacted together following the procedure detailed for thecompound of Example 2 which gave the title compound as a pale yellowsolid (0.18 g, 72%).

δH NMR (d₃ MeOD): 8.03 (1H, d, J=6.0 Hz), 7.99 (1H, s), 7.71 (1H, m),7.46-7.20 (7H, m), 6.25 (1H, d, J=6.0 Hz), 6.16 (1H, br-s), 3.87 (2H,m), 3.65 (2H, m), 3.33 (2H, m), 1.29 (2H, m), 0.51 (2H, m), 0.20 (2H,m).

LCMS (ES⁺) Retention time 2.61 minutes, 425 (MH)⁺.

EXAMPLE 43-[4-(4Benzyl-3-oxo-2-phenyl-piperazin-1-yl)-pyrimidin-2-ylamino]-benzonitrile

Intermediate 5, (0.39 g, 1.03 mmol) and 3-cyanoaniline (0.14 g, 1.17mmol) were reacted together following the procedure detailed for thecompound of Example 2, which gave the title compound as a pale yellowsolid (0.28 g, 58%).

δH NMR (d₃ MeOD): 7.90 (1H, d, J=5.9 Hz), 7.75 (1H, s), 7.56 (1H, m),7.55-7.06 (11H, m), 6.82 (1H, m), 6.31 (1H, d, J=6.3 Hz), 6.09 (1 H,br-s), 4.67 (1H, d, J=14.7 Hz), 4.43 (1H, d, J=14.7 Hz), 3.81 (1H,br-s), 3.53-3.24 (4H, m),

LCMS (ES⁺) Retention time 2.79 minutes, 461 (MH)⁺.

EXAMPLE 53-[4-(4Allyl-3-oxo-2-phenyl-piperazin-1-yl)-pyrimidin-2-ylamino]-benzonitrile

Intermediate 6, (0.10 g, 0.30 mmol) and 3-cyanoaniline (0.05 g, 0.45mmol) were reacted together following the procedure detailed for thecompound of Example 2, with the addition of an equivalent of tosic acidwhich eventually gave the title compound as a white solid (0.07 g, 57%).

δH NMR (d₃ MeOD): 7.93 (1H, d, J=6.1 Hz), 7.87 (1H, s), 7.61 (4H, m),7.35-7.10 (4H, m) 6.16 (1H, d, J=6.1 Hz), 6.08 (1H, br-s), 5.68 (1H, m),5.05 (2H, m), 4.09-3.72 (4H, m), 3.41 (2H, m).

LCMS (ES⁺) Retention time 2.56 minutes, 411 (MH)⁺.

EXAMPLE 63-[4-(2-Phenyl-piperidin-1-yl)-pyrimidin-2-ylamino]-benzonitrile

Intermediate 16, (0.20 g, 0.73 mmol) in dry ethoxyethanol (5 mL) and3-cyanoaniline (0.07 g, 0.80 mmol), were heated to 100° under anatmosphere of nitrogen and stirred for 18 hours. The mixture was cooledand evaporated in vacuo to give a brown oil. The oil was purified bychromatography (5-20% MeOH in EtOAc/silica) to give the title compoundas a white solid (0.23 g, 84%).

δH NMR (d₃ MeOD): 7.78 (2H, m), 7.54 (1H, d, J=2.4 Hz), 7.14-7.36 (9H,m), 6.52 (1H, u, J=7.4 Hz), 5.77 (1H, br-s), 4.26 (1H, m), 3.20 (1H, m),2.39 (1H, m), 1.50-2.04 (5H, m).

LCMS (ES⁺) Retention time 2.68 minutes, 356 (MH)⁺.

EXAMPLE 7 Phenyl-[4-(2-Phenyl-piperidin-1-yl)-pyrimidin-2-yl]-amine

Intermediate 16, (0.20 g, 0.73 mmol) and aniline (0.08 g, 0.80 mmol)were reacted together following the procedure detailed for the compoundof Example 6, which gave the title compound as a white solid (0.22 g,82%).

δHNMR (d₃ MeOD): 7.68 (1H, d, J=7.5 Hz), 7.06-7.35 (10H, m), 6.47 (1H,d, J=7.5 Hz), 5.79 (1H, br-s), 4.30 (1H, m), 3.20 (1H, m), 2.34 (1H, m),1.92 (1H, m), 1.53 (4H, m).

LCMS (ES) Retention time 2.66 minutes, 331 (MH)⁺.

EXAMPLE 8 Benzyl-[4-(2-phenyl-piperidin-1-yl)-pyrimidin-2-yl]-amine

Intermediate 16, (0.20 g, 0.73 mmol) in dry ethoxyethanol (10 mL) wastreated with sodium bicarbonate (0.31 g, 3.65 mmol) and benzylamine(0.47 g, 4.39 mmol) in one portion at room temperature, under anatmosphere of nitrogen. The suspension was heated to 120° for 48 hr.then cooled, the mixture filtered and the filtrate evaporated in vacuoto a yellow gum. The gum was purified by chromatography (1-20% MeOH inEtOAc-silica) to give the title compound as a beige solid (0.12 g, 49%).

δH NMR (d₃ MeOD): 7.60 (1H, d, J=6.3 Hz), 7.24-7.04 (10H, m), 5.90 (1H,d, J=6.3 Hz), 5.68 (1H, br-s), 4.36(2H, dd, J=15.9 and 37.7 Hz), 4.14(1H, m), 2.85 (1H, m), 2.23 (1H, dd, J=2.0 and 13.48 Hz), 1.37-1.80 (6H,m).

LCMS (ES⁺) Retention time 2.69 minutes, 345 (MH)⁺.

EXAMPLE 9(3R)-(3Chloro-phenyl)-[4-(3-phenyl-morpholin-4-yl-pyrimidin-2-yl]-amine

Intermediate 19, (0.18 g, 0.65 mmol) and 3-chloroaniline (0.10 g, 0.72mmol) were reacted together following the procedure detailed for thecompound of Example 6, which gave the title compound as a white solid(0.17 g, 99%).

δH NMR (u₃ MeOD): 7.87 (1H, d, J=7.4 Hz), 7.58 (1H, s), 7.15-7.41 (8H,m), 6.61 (1H, d, J=7.5 Hz), 5.65 (1H, s), 4.48 (1H, d, J=12.3 Hz), 4.23(1H, br-d, J=13.3 Hz), 4.00 (2H, m), 3.74 (1H, m), 3.51 (1H, m). LCMS(ES⁺) Retention time 2.65 minutes, 367 (MH)⁺. (Data and experimental arethe same for the S-enantiomer)

EXAMPLE 10(3R)-(2,6-Difluoro-benzyl)-[4-(3-phenyl-morpholin-4-yl)-pyrimidin-2-yl]-amine

Intermediate 19, (0.18 g, 0.65 mmol) and 2,6-difluorobenzylamine (0.56g, 3.93 mmol) were reacted together following the procedure detailed forthe compound of Example 8, which gave the title compound as an off-whitesolid (0.19 g, 76%).

δH NMR (d₃ MeOD): 7.64 (1H, d, J=6.5 Hz), 7.24-7.11 (6H, m), 6.77 (2H,m), 6.00 (1H, d, J=6.5 Hz), 5.55 (1H, s), 4.51 (2H, s), 4.35 (1H, d,J=12.0 Hz), 4.06 (1H, m), 3.78 (2H, m), 3.52 (1H, m), 3.19 (1H, m), LCMS(ES⁺) Retention time 2.54 minutes, 383 (MH)⁺. (Data and experimental arethe same for the S-enantiomer)

EXAMPLE 11(1R,3R)-(1-Phenyl-ethyl)-[4-(3-phenyl-morpholin-4-yl)-pyrimidin-2-yl-amine

Intermediate 19, (0.18 g, 0.65 mmol) and (R)-methylbenzylamine (0.47 g,3.93 mmol) were reacted together following the procedure detailed forthe compound of Example 8, which gave the title compound as an off-whitesolid (0.10 g, 43%).

δH NMR (d₃ MeOD): 7.63 (1H, br-s), 7.22-7.11 (10H, m), 5.88 (1H, d,J=6.3 Hz), 5.42 (1H, br-s), 4.91 (1H, dd, J=7.0 and 14.0 Hz), 4.30 (1H,d, J=12.0 Hz), 3.85 (3H, m), 3.40 (1H, m), 3.10 (1H, m), 1.37 (3H, d,J=7.0 Hz).

LCMS (ES⁺) Retention time 2.58 minutes, 361 (MH)⁺. (Data andexperimental are the same for the (S),(S)-enantiomer)

EXAMPLE 12(3R,1S)(1-Phenyl-ethyl)-[4-(3-phenyl-morpholin-4-yl)-pyrimidin-2-yl]-amine

Intermediate 19, (0.18 g, 0.65 mmol) and (S)-methylbenzylamine (0.47 g,3.93 mmol) were reacted together following the procedure detailed forthe compound of Example 8, which gave the title compound as an off-whitesolid (0.11 g, 45%).

δH NMR (d₃ MeOD): 7.63 (1H, d, J=6.1 Hz), 7.22-7.06 (10H, m), 5.94 (1H,d, J=6.2 Hz), 5.30 (1H, br-s), 4.79 (1H, m), 4.23 (1H, d, J=12.0 Hz),3.80 (1H, m), 3.77 (1H, m), 3.58 (1H, m), 3.46 (1H, m), 3.11 (1H, m),1.34 (3H, d, J=6.9 Hz).

LCMS (ES⁺) Retention time 2.59 minutes, 361 (MH)⁺. (Data andexperimental are the same for the (S),(R)-enantiomer)

EXAMPLE 133-(4-Fluoro-phenyl)-4-[2-(4-nitro-phenylamino)pyrimidin-4-yl]-piperazin-2-one

Prepared as for the compound of Example 2 from 4-nitroaniline andIntermediate 9.

δH NMR (d₆ DMSO): 9.99(1H, br-s), 8.39(1H, br-s), 8.13-8.06(3H, m),7.86-7.83(2H, d, J=8.81 Hz), 7.51-7.46(2H, m), 7.25-7.19(2H, m), 6.39(1H, br-s), 5.90(1H, br-s), 3.97(1H, br-s), 3.75-3.70(1H, m),3.42-3.28(2H, m).

LCMS (ES⁺) retention time 2.581 minutes 409(MH)⁺.

EXAMPLE 143-(4-Fluoro-phenyl)-4-[2-(4-fluoro-3-trifluoromethyl-phenylamino)-pyrimidin-4-yl]-piperazin-2-one

Prepared as for the compound of Example 2 from4-fluoro-3-trifluoromethylaniline and Intermediate 9.

δH NMR (d₅ DMSO): 9.50(1H, s), 8.36(1H, br-s), 8.21(1H, vbr-s), 8.05(1H,d, J=6.01 Hz), 7.86(1H, vbr-s), 7.47-7.42(2H, m), 7.33(1H, t, J=9.61Hz), 7.19(2H, t, J=8.99 Hz), 6.29(1H, m), 5.92(1H, br-s), 3.99-3.97(1H,m), 3.68-3.57(1H, m), 3.50-3.13(2H,-m).

LCMS (ES⁺) Retention time 2.618 minutes, 450(MH)⁺.

EXAMPLE 15(3-Chloro-phenyl)-[4-(2-phenyl-piperazin-1-yl)-pyrimidin-2-yl]-amine

Intermediate 13, (100 mg, 0.21 mmol) in DCM (5 mL) was treated withtrifluoroacetic acid (1 mL) and stirred at room temperature for twohours. The reaction mixture was concentrated and partitioned between DCMand saturated sodium hydrogen carbonate solution. The organic phase wasseparated, dried over sodium sulphate and concentrated in vacuo, toyield the title compound.

δH NMR (d₆ DMSO): 9.30(1H, s), 8.04(1H, d, J=6.1 Hz), 7.97(1H, d, J=1.6Hz), 7.56(1H, d, J=8.26 Hz), 7.40-7.34(4H, m), 7.29-7.22(2H, m),6.94-6.91(1H, m), 6.32(1H, d, J=6.18 Hz), 5.58(1H, br-s), 4.23(1H, br-d,J=12.3 Hz), 3.52(1H, d, J=12.6 Hz), 3.23-3.09(2H, m), 3.03(1H, br-d,J=10.3 Hz).

LCMS (ES⁺) Retention time 1.186 minutes, 366(MH)⁺.

EXAMPLE 16 4-(2-Benzylaminopyrimidin-4-yl)-3-phenyl-piperazin-2-one

Intermediate 2, (0.2 g, 0.69 mmol) in dioxane (4 mL) was treated withbenzylamine (0.090 g, 0.84 mmol) and heated at 100° for 24 hours. Thereaction mixture was cooled and concentrated in vacuo and the residuepurified by chromatography (3-20% MeOH in DCM-silica) to give the titlecompound as a white solid (170 mg).

δH NMR (CDCl₃): 8.23(1H, s), 7.83(1H, d, J=5.88 Hz), 7.37-7.15(10H, m),5.98(1H, d, J=5.2 Hz), 5.93(1H, br-s), 4.44-4.32(2H, m), 3.85(1H, br-s),3.54-3.51(1H, m), 3.31(2H, s), 3.21-3.15 (1H, m).

MS (ES⁺) 360(MH)⁺.

EXAMPLE 17 3-Phenyl-4-(2-phenylaminopyrimidin-4-yl)-piperazin-2-one

Intermediate 2, (0.2 g, 0.69 mmol) in dioxane (4 mL) was treated withaniline (0.080 g, 0.86 mmol) and heated at 100° for 24 hours. Thereaction mixture was cooled and concentrated in vacuo and the residuepurified by chromatography (3-20% MeOH in DCM-silica) to give the titlecompound as a white solid (185 mg).

δH NMR (CDCl₃): 8.48(1H, s), 8.09(1H, br-s), 7.59-7.11(11H, m), 6.59(1H,br-s), 5.89(1H, br-s), 4.03(1H, br-s), 3.89-3.70(1H, m), 3.56-3.26 (2H,m).

MS (ES⁺) 346(MH)⁺.

EXAMPLES 18-31

The following general procedure was used to prepare the compounds ofExamples 18-31 below. A solution of the appropriate substituted aniline(0.77 mmol) and Intermediate 2 (0.7 mmol) in 2-ethoxyethanol (5 mL) washeated to 120° under nitrogen in a Radleys Carousel reaction station for16 h. Solvent was removed in vacuo and the crude product purified bychromatography (5-10% MeOH in DCM-silica) to give the appropriate titlecompound.

EXAMPLE 184-[2-(2-Methylphenylamino)pyrimidin-4-yl]-3-phenyl-piperazin-2-one

From o-toluidine to give the title compound as a solid.

δH NMR (d₆ DMSO): 8.27(1H, s), 8.17(1H, s), 7.94(1H, d, J=5.7 Hz), 7.42(1H, m), 7.28-7.32(5H, m), 7.15 (1H, m), 6.95-7.09 (2H, m), 6.16 (1H, d,J=5.7 Hz), 5.89(1H, m), 3.92 (1H, m), 3.65 (1H, m), 3.40 (1H, m), 3.25(1H, m), 2.18 (3H, s)

LCMS (ES⁺) Retention time 2.432 minutes, 360 (MH)⁺.

EXAMPLE 194-[2(3-Methylphenylamino)pyrimidin-4-yl]-3-phenyl-piperazin-2-one

From m-toluidine to give the title compound as a solid.

δH NMR (d₆ DMSO): 9.10(1H, s), 8.30(1H, s), 8.02(1H, d, J=6 Hz),7.3-7.5(6H, m), 7.03-7.00(1H, m), 6.98(1H, m), 6.68(1H, d, J=7.5 Hz),6.13(1H, d, J=6 Hz), 5.80-5.95(1H, m), 3.90 (1H, m), 3.60 (1H, m), 3.30(1H, m), 3.11 (1H, m), 2.17 (3H, s)

LCMS (ES⁺) Retention time 2.562 minutes, 360 (MH)⁺.

EXAMPLE 204-[2-(3-Cyanophenylamino)pyrimidin-4-yl]-3-phenyl-piperazin-2-one

From 3-aminobenzonitrile to give the title compound as a solid.

δH NMR (d₆ DMSO): 8.60(1H, s), 8.25-8.27(1H, d, J=6.6 Hz), 8.10(1H, s),7.90(1 H, m), 7.30-7.60(6H, m), 6.98(1H, m), 6.67-6.74(1H, m),6.10-6.15(1H, m), 4.27 (1H, m), 4.0 (1H, m), 3.50 (2H, br-m), 3.10 (1H,m)

LCMS (ES⁺) Retention time 2.309 minutes, 371 (MH)⁺.

EXAMPLE 214-[2-(3-Nitrophenylamino)pyrimidin-4-yl]-3-phenyl-piperazin-2-one

From 3-nitroaniline to give the title compound as a solid.

δH NMR (d₆ DMSO): 9.50(1H, s), 8.10(1H, s), 8.15 (1H, br-s), 7.90(1H, d,J=5.5 Hz), 7.76(1H, dd, J=8.2, 1.0 Hz), 7.52(1H, m), 7.28-7.09(6H, m),6.12(1H, d, J=5.5 Hz), 5.75(1H, br-m), 3.90 (1H, m), 3.70 (1H, m), 3.30(1H, m), 3.10 (1H, m)

LCMS (ES⁺) Retention time 2.514 minutes, 393 (MH)⁺.

EXAMPLE 224-[2-(4-Cyano-phenylamino)pyrimidin-4-yl]-3-phenyl-piperazin-2-one

From p-aminobenzonitrile to give the title compound as a solid.

δH NMR (d₆ DMSO): 9.8(1H, s), 8.34(1H, s), 8.1-8.14(1H, m),7.30-7.40(5H, m), 7.0 (3H, m), 6.83-6.98(1H, m), 6.50(1H, m), 5.88(1H,m), 3.90(1H, m), 3.60(1H, m), 3.50(2H, br-m)

LCMS (ES⁺) Retention time 2.511 minutes, 371 (MH)⁺.

EXAMPLE 234-[2-(4-Methoxyphenylamino)pyrimidin-4yl]-3-phenyl-piperazin-2-one

From p-anisidine to give the title compound as a solid.

δH NMR (d6 DMSO): 9.7(1H, s), 8.26(1H, s), 7.84(1H, d, J=6 Hz),7.0-7.30(3H, br-m), 6.93(2H, m), 6.80(2H, d, J=9 Hz), 6.56(2H, d, J=5Hz), 6.26(1H, d, J=6 Hz) 5.73(1H, m), 3.80 (1H, m), 3.60 (1H, m), 3.57(3H, s), 3.30 (2H, br-m).

LCMS (ES⁺) Retention time 2.254 minutes, 376 (MH)⁺.

EXAMPLE 244-[2-(2-Methoxyphenylamino)pyrimidin-4-yl]-3-phenyl-piperazin-2-one

From o-anisidine to give the title compound as a solid.

δH NMR (CDCl₃): 8.15(1H, d, J=7 Hz), 7.95(1H, d, J=6 Hz), 7.19-7.46(6H,m), 6.90(3H, m), 6.85(1H, m), 5.87-5.89(2H, m), 4.10 (1H, br-m), 3.95(3H, s), 3.90 (1H, br-m), 3.40 (2H, br-m)

LCMS (ES⁺) Retention time 2.286 minutes, 376 (MH)⁺.

EXAMPLE 254-[2-(3-Methoxy-phenylamino)pyrimidin-4-yl]-3-phenyl-piperazin-2-one

From m-anisidine to give the title compound as a solid.

δH NMR (d₆ DMSO): 8.40 (1H, s), 8.10(1H, s), 7.40(6H, br-m), 7.15(2H,m), 7.10(1H, m), 6.80(1H, m), 6.40(1H, m), 4.0(1H, m) 3.90(1H, m), 3.68(3H, s), 3.4 (2H, m)

LCMS (ES⁺) Retention time 2.295 minutes, 376 (MH)⁺.

EXAMPLE 264-[2-(3,4,5-trimethoxyphenylamino)pyrimidin-4-yl]-3-phenyl-piperazin-2-one

From 3,4,5-trimethoxyaniline to give the title compound as a solid.

δH NMR (d₆ DMSO): 9.4(1H, s), 8.30(1H, d, J=6 Hz), 7.75 (5H, m),7.50(2H, s), 6.50(1H, s), 4.30 (1H, m), 4.05(6H, s), 3.95 (3H, s), 3.75(2H, m), 3.50(1H, m)

LCMS (ES⁺) Retention time 2.257 minutes, 436 (MH)⁺.

EXAMPLE 274-[2-(4Chlorophenylamino)pyrimidin-4-yl]-3-phenyl-piperazln-2-one

From p-chloroaniline to give the title compound as a solid.

δH NMR (d₆ DMSO): 9.1(1H, s), 8.15(1H, s), 7.80 (1H, d, J=6 Hz), 7.30(2H, m), 7.30-7.10(5H, m), 6.90(2H, m), 5.90(1H, d, J=6 Hz), 5.60(1H, d,J=6 Hz), 5.60(1H, m), 3.70(1H, br-m), 3.5 (1H, br-m), 3.25(1H, m).

LCMS (ES⁺) Retention time 2.385 minutes, 380 (MH)⁺.

EXAMPLE 284-[2(3-Chlorophenylamino)pyrimidin-4-yl]-3-phenyl-piperazin-2-one

From m-chloroaniline to give the title compound as a solid.

δH NMR (d₆ DMSO): 9.3(1H, s), 8.25(1H, s), 8.15(1H, d, J=6 Hz), 7.80(1H,s), 7.25-7.5(6H, m), 6.95(1H, m), 6.80(1H, s), 6.25(1H, d, J=6 Hz),6.05(1H, m), 3.90 (1H, m), 3.70 (1H, m), 3.25(1H, m)

LCMS (ES⁺) Retention time 2.404 minutes, 380 (MH)⁺.

EXAMPLE 294-[2-(3-Fluorophenylamino)pyrimidin-4-yl]-3-phenyl-piperazin-2-one

From m-fluoroaniline to give the title compound as a solid.

δH NMR (d₆ DMSO): 9.1(1H, s), 8.10(1H, s), 7.90(1H, d, J=6 Hz), 7.50(1H,m), 7.0-7.25(6H, br-m), 6.95(1H, m), 6.50(1H, m), 6.15(1H, d, J=6 Hz),5.90(1H, m), 3.75(1H, m), 3.55(1H, m) 3.25(2H, m)

LCMS (ES⁺) Retention time 2.518 minutes, 364 (MH)⁺.

EXAMPLE 304-[2-(2-Fluorophenylamino)pyrimidin-4-yl]-3-phenyl-piperazin-2-one

From o-fluoroaniline to give the-title compound as a solid.

δH NMR (d₆ DMSO): 8.47(1H, s), 8.30(1H, s), 8.00 (1H, d, J=6 Hz),7.70(1H, m), 7.37-7.30(4H, m), 7.05(2H, m), 6.25(1H, d, J=6 Hz),5.95(1H, m), 3.90(1H, m), 3.66(1H, m), 3.20 (2H, br-m)

LCMS (ES⁺) Retention time 2.415 minutes, 364 (MH)⁺.

EXAMPLE 314-[2-(4-Fluorophenylamino)pyrimidin-4-yl]-3-phenyl-piperazin2-one

From p-fluoroaniline to give the title compound as a solid.

δH NMR (d₆ DMSO): 9.97(1H, s), 8.42(1H, s), 8.01 (1H, d, J=6 Hz),7.36-7.41(5H, m), 7.35(1H, m), 6.90-6.98(2H, m), 6.77(1H, d, J=6 Hz),5.80-5.95(1H, m), 3.90 (1H, m), 3.80(1H, m), 3.30 (2H, br-m)

LCMS (ES⁺) Retention time 2.296 minutes, 364 (MH)⁺

EXAMPLES 32-86

The compounds of Examples 32-86 were prepared according to the followingprocedure.

The appropriate chloropyrimidine and the appropriate amine with sodiumhydrogen carbonate (5 equivalents) were dissolved in ethoxyethanol (0.5mL) and heated at 120° for two days in a Zinser block. After cooling thereaction was diluted with DMSO and filtered, the filtrate was purifiedby HPLC to yield the appropriate title compound.

EXAMPLE 324-[2-(1,3-Dimethyl-butylamino)-pyrimidin-4-yl]-3-phenyl-piperazin-2-one

Prepared as above using Intermediate 2 and 1,3-dimethyl-butylamine.

LCMS (ES⁺) Retention time 2.41 minutes, 354 (MH)⁺

EXAMPLE 333-Phenyl-4-[2-(3,3,3-trifluoro-propylamlno)-pyrimidin-4-yl]-piperazin-2-one

Prepared as above using Intermediate 2 and 3,3,3-trifluoro-propylamine.

LCMS (ES⁺) Retention time 2.26 minutes, 366 (MH)⁺.

EXAMPLE 344-[2-(3-Methoxy-propylamino)-pyrimidin-4-yl]-3-phenyl-piperazin-2-one

Prepared as above using Intermediate 2 and 3-methoxy-propylamine.

LCMS (ES⁺) Retention time 2.08 minutes, 342 (MH)⁺.

EXAMPLE 354-[2-(3-Isopropoxy-propylamino)-pyrimidin-4-yl]-3-phenyl-piperazin-2-one

Prepared as above using Intermediate 2 and 3-isopropoxy-propylamine.

LCMS (ES⁺) Retention time 2.28 minutes, 370(MH)⁺.

EXAMPLE 36 4-(2-Allylamino-pyrimidin-4-yl)-3-phenyl-piperazin-2-one

Prepared as above using Intermediate 2 and allylamine.

LCMS (ES⁺) Retention time 2.11minutes, 310(MH)⁺.

EXAMPLE 374-[2-(Cyclopropylmethyl-amino)-pyrimidin-4-yl]-3-phenyl-piperazin-2-one

Prepared as above using Intermediate 2 and cyclopropylmethylamine.

LCMS (ES⁺) Retention time 2.22 minutes, 324 (MH)⁺.

EXAMPLE 38(3R)-[4-(3-Phenyl-morpholin-4-yl)-pyrimidin-2-yl]-thiophen-2-ylmethyl-amine

Prepared as above using Intermediate 19 and 2-aminomethyl-thiophene.

LCMS (ES⁺) Retention time 2.48 minutes, 353 (MH)⁺.

EXAMPLE 394-[2-(2-Methoxy-ethylamino)-pyrimidin-4-yl]-3-phenyl-piperazin-2-one

Prepared as above using Intermediate 2 and 2-methoxyethylamine.

LCMS (ES⁺) Retention time 1.77 minutes, 328 (MH)⁺.

EXAMPLE 40 4-(2-Isobutylamino-pyrimidin-4-yl)-3-phenyl-piperazin-2-one

Prepared as above using Intermediate 2 and isobutylamine.

LCMS (ES⁺) Retention time 2.28 minutes, 326 (MH)⁺.

EXAMPLE 41{4-[4-(3-Oxo-2-phenyl-piperazin-1-yl)-pyrimidin-2-ylamino]-butyl}-carbamicacid tert-butyl ester

Prepared as above using Intermediate 2 andtert-butyloxycarbonyl-1,4-diaminobutane

LCMS (ES⁺) Retention time 2.37 minutes, 441 (MH)⁺.

EXAMPLE 42 4-(2-Pentylamino-pyrimidinyl)-3-phenyl-piperazin-2-one

Prepared as above using Intermediate 2 and pentylamine.

LCMS (ES⁺) Retention time 2.36 minutes, 340 (MH)⁺.

EXAMPLE 434-(2-Cyclopentylamino-pyrimidin-4-yl)-3-phenyl-piperazin-2-one

Prepared as above using Intermediate 2 and cyclopentylamine.

LCMS (ES⁺) Retention time 2.28 minutes, 338 (MH)⁺.

EXAMPLE 444-[2-(3-Methyl-butylamino)-pyrimidin-4-yl]-3-phenyl-piperazin-2-one

Prepared as above using Intermediate 2 and 3-methyl-butylamine.

LCMS (ES⁺) Retention time 2.35 minutes, 340 ((MH)⁺.

EXAMPLE 45(3R)-(2,3-Difluoro-benzyl)-4-(3-phenyl-morpholin-4-yl)-pyrimidin-2-yl]-amine

Prepared as above using Intermediate 19 and 2,3-difluorobenzylamine.

LCMS (ES⁺) Retention time 2.52 minutes, 383 (MH)⁺.

EXAMPLE 463-Phenyl-4-[2-(3-phenyl-propylamino)-pyrimidin-4-yl]-piperazin-2-one

Prepared as above using Intermediate 2 and 3-phenyl-1-propylamine.

LCMS (ES⁺) Retention time 2.42 minutes, 388 (MH)⁺.

EXAMPLE 473-Phenyl-4-[2-(4-phenyl-butylamino)-pyrimidin-4-yl]-piperazin-2-one

Prepared as above using Intermediate 2 and 4-phenyl-butylamine.

LCMS (ES⁺) Retention time 2.48 minutes, 402 (MH)⁺.

EXAMPLE 484-[2-(1-Methyl-butylamino)-pyrimidin-4-yl]-3-phenyl-piperazin-2-one

Prepared as above using Intermediate 2 and 1-methyl-butylamine.

LCMS (ES⁺) Retention time 2.34 minutes,340 (MH)⁺.

EXAMPLE 49 4-(2-Phenethylamino-pyrimidin-4-yl)-3-phenyl-piperazin-2-one

Prepared as above using Intermediate 2 and 2-phenethylamine.

LCMS (ES⁺) Retention time 2.35 minutes, 374 (MH)⁺.

EXAMPLE 50(3R)Indan-1-yl-[4-(3-phenyl-morpholin-4-yl)-pyrimidin-2-yl]-amine

Prepared as above using Intermediate 19 and indan-1-ylamine.

LCMS (ES⁺) Retention time 2.57 minutes, 373 (MH)⁺.

EXAMPLE 514-{2-[2-(4-Hydroxy-phenyl)-ethylamino]-pyrimidin-4-yl]-3-phenyl-piperazin-2-one

Prepared as above using Intermediate 2 and2-(4-Hydroxy-phenyl)-ethylamine.

LCMS (ES⁺) Retention time 2.17 minutes, 390 (MH)⁺.

EXAMPLE 52 4-(2-Cyclobutylamino-pyrimidin-4-yl)-3-phenyl-piperazin-2-one

Prepared as above using Intermediate 2 and cyclo-butylamine.

LCMS (ES⁺) Retention time 2.21 minutes, 324 (MH)⁺.

EXAMPLE 534-[2-(2-Methyl-butylamino)-pyrimidin-4-yl]-3-phenyl-piperazin-2-one

Prepared as above using Intermediate 2 and 2-methyl-butylamine.

LCMS (ES⁺) Retention time 2.34 minutes, 340 (MH)⁺.

EXAMPLE 544-{2-[2(5-Methoxy-1H-indol-3-yl)-ethylamino]-pyrimidin-4-yl)-3-phenyl-piperazin-2-one

Prepared as above using Intermediate 2 and2-(5-methoxy-1H-indol-3-yl)-ethylamine.

LCMS (ES⁺) Retention time 2.33 minutes, 443 (MH)⁺.

EXAMPLE 554-(2-[2-(1H-Indol-3-yl)-ethylamino]-pyrimidin-4-yl)-3-phenyl-piperazin-2-one

Prepared as above using Intermediate 2 and 2-(1H-indol-3-yl)-ethylamine.

LCMS (ES⁺) Retention time 2.35 minutes, 413 (MH)⁺.

EXAMPLE 564-[2-(2-Diethylamino-ethylamino)-pyrimidin-4-yl]-3-phenyl-piperazin-2-one

Prepared as above using Intermediate 2 and N,N-diethylethylenediamine.

LCMS (ES⁺) Retention time 0.87 minutes, 369 (MH)⁺.

EXAMPLE 57(3S)-Benzo[b]thiophen-3-ylmethyl-[4-(3-phenyl-morpholin-4-yl)-pyrimidin-2-yl]-amine

Prepared as above using Intermediate 19(S) and benzo[b]thiophene-3-ylmethylamine.

LCMS (ES⁺) Retention time 2.64 minutes, 403 (MH)⁺.

EXAMPLE 58(3S)-[4-(3-Phenyl-morpholin-4-yl)-pyrimidin-2-yl]-(1,3,5-trimethyl-1H-pyrazol-4-ylmethyl)-amine

Prepared as above using Intermediate 19(S) and1,3,5-trimethyl-1H-pyrazol-4-ylmethylamine.

LCMS (ES⁺) Retention time 2.36 minutes, 379 (MH)⁺.

EXAMPLE 59(3S)-2,4-Dichloro-benzyl)-[4-(3-Phenyl-morpholin-4-yl)pyrimidin-2-yl]-amine

Prepared as above using Intermediate 19(S) and 2,4-dichlorobenzyl amine.

LCMS (ES⁺) Retention time 2.68 minutes, 415 (MH)⁺.

EXAMPLE 60(3S)-(1-Methyl-1H-pyrrol-2-ylmethyl)-[4-(3-phenyl-morpholin-4-yl]-pyrimidin-2-yl]-amine

Prepared as above using Intermediate 19(S) and1-methyl-1H-pyrrol-2-ylmethylamine.

LCMS (EC⁺) Retention time 2.48 minutes, 350 (MH)⁺.

EXAMPLE 61(3S)-[4-(3-Phenyl-morpholin-4-yl)-pyrimidin-2-yl]-(1,2,3,4-tetrahydro-naphthalen-1-yl)-amine

Prepared as above using Intermediate 19(S) and(1,2,3,4-tetrahdro-naphthalen-1-yl)amine.

LCMS (ES⁺) Retention time 2.67 minutes, 387 (MH)⁺.

EXAMPLE 62(3S)-Indan-1-yl-[4-(3-phenyl-morpholin-4-yl)pyrimidin-2-yl]-amine

Prepared as above using Intermediate 19(S) and indan-1-ylamine.

LCMS (ES⁺) Retention time 2.63 minutes, 373 (MH)⁺.

EXAMPLE 63(3S)-(2-Chloro-benzyl)-[4-(3-phenyl-morpholin-4-yl)-pyrimidin-2-yl]-amine

Prepared as above using Intermediate 19(S) and 2-chlorobenzylamine.

LCMS (ES⁺) Retention time 2.59 minutes, 381 (MH)⁺.

EXAMPLE 64(3S)-(2,4-Dichloro-benzyl)-[4(3-phenyl-morpholin-4yl)-pyrimidin-2-yl]-amine

Prepared as above using Intermediate 19(S) and 2,4-dichlorobenzylamine.

LCMS (ES⁺) Retention time 2.68 minutes, 415 (MH)⁺.

EXAMPLE 65(3S)-(2-Methoxy-benzyl)-[4-(3-phenyl-morpholin-4-yl)-pyrimidin-2-yl]-amine

Prepared as above using Intermediate 19(S) and 2-methoxybenzylamine.

LCMS (ES⁺) Retention time 2.57 minutes, 377 (MH)⁺.

EXAMPLE 66(3S)-(2-Methyl-benzyl)-[4-(3-phenyl-morpholin-4-yl)-pyrimidin-2-yl]-amine

Prepared as above using Intermediate 19(S) and 2-methylbenzylamine.

LCMS (ES⁺) Retention time 2.59 minutes, 361 (MH)⁺.

EXAMPLE 67(3S)-(2,5-Difluoro-benzyl)-[4(3-phenyl-morpholin-4-yl)-pyrimidin-2-yl]-amine

Prepared as above using Intermediate 19(S) and 2,5-difluorobenzylamine.

LCMS (ES⁺) Retention time 2.55 minutes, 383 (MH)⁺.

EXAMPLE 68(3S)-[4-(3-Phenyl-morpholin-4-yl)-pyrimidin-2-yl]-(2-trifluoromethyl-benzyl)-amine

Prepared as above using Intermediate 19(S) and2-trifluoromethylbenzylamine.

LCMS (ES⁺) Retention time 2.64 minutes, 415 (MH)⁺.

EXAMPLE 69(3S)-(2-Chloro-6-fluoro-benzyl)-[4-(3-phenyl-morpholin-4-yl)-pyrimidin-2-yl]-amine

Prepared as above using Intermediate 19(S) and2-chloro-6-fluorobenzylamine.

LCMS (ES⁺) Retention time 2.59 minutes, 399 (MH)⁺.

EXAMPLE 70(3S)-(2,3-Dichloro-benzyl)-[4-(3-phenyl-morpholin-4-yl)pyrimidin-2-yl-amine

Prepared as above using Intermediate 19(S) and 2,3-dichlorobenzylamine.

LCMS (ES⁺) Retention time 2.66 minutes, 415 (MH)⁺.

EXAMPLE 71(3S)-(2Chloro-6-methyl-benzyl)-[4-(3-phenyl-morpholin-4-yl)-pyrimidin-2-yl]-amine

Prepared as above using Intermediate 19(S) and2-chloro-6-methylbenzylamine.

LCMS (ES⁺) Retention time 2.66 minutes, 395 (MH)⁺.

EXAMPLE 72(3S)-(4-Fluoro-2-trifluoromethyl-benzyl)-[4-(3-phenyl-morpholin-4-yl)-pyrimidin-2-yl]-amine

Prepared as above using Intermediate 19(S) and4-fluoro-2-trifluoromethylbenzylamine.

LCMS (ES⁺) Retention time 2.67 minutes, 433 (MH)⁺.

EXAMPLE 73(3S)(2,3-Difluoro-benzyl)[4-(3-Phenyl-morpholin-4-yl)-pyrimidin-2-yl]-amine

Prepared as above using Intermediate 19(S) and 2,3-difluorobenzylamine.

LCMS (ES⁺) Retention time 2.56 minutes, 383 (MH)⁺.

EXAMPLE 74(3S)(2,3-Dimethyl-benzyl)-[4-(3-Phenyl-morpholin-4-yl)-pyrimidin-2-yl]-amine

Prepared as above using Intermediate 19(S) and 2,3-dimethylbenzylamine.

LCMS (ES⁺) Retention time 2.65 minutes, 375 (MH)⁺.

EXAMPLE 75(3S)(2-Nitro-benzyl)-[4-(3-phenyl-morpholin-4-yl)-pyrimidin-2-yl]-amine

Prepared as above using Intermediate 19(S) and 2-nitrobenzyl amine.

LCMS (ES⁺) Retention time 2.51 minutes, 392 (MH)⁺.

EXAMPLE 76(3S)-[4-(3-Phenyl-morpholin-4-yl)-pyrimidin-2-yl](2,3,4-trifluoro-benzyl)-amine

Prepared as above using Intermediate 19(S) and2,3,4-trifluorobenzylamine.

LCMS (ES⁺) Retention time 2.60 minutes, 401(MH)⁺.

EXAMPLE 77(3S)-[4(3-Phenyl-morpholin-4-yl)-pyrimidin-2-yl]-(2,3,6-trifluoro-benzyl)-amine

Prepared as above using Intermediate 19(S) and2,3,6-trifluorobenzylamine.

LCMS (ES⁺) Retention time 2.56 minutes, 401 (MH)⁺.

EXAMPLE 78(3S)-(2-Methylsulfanyl-benzyl)-[4-(3-Phenyl-morpholin-4-yl)-pyrimidin-2-yl]-amine

Prepared as above using Intermediate 19(S) and2-methyl-sulphanyl-benzylamine.

LCMS (ES⁺) Retention time 2.60 minutes, 393 (MH)⁺.

EXAMPLE 79(3S)-(6-Chloro-2-fluoro-3-methyl-benzyl)-[4-(3-phenyl-morpholin-4-yl)-pyrimidin-2-yl]-amine

Prepared as above using Intermediate 19(S) and6-chloro-2-fluoro-3-methylbenzylamine.

LCMS (ES⁺) Retention time 2.66 minutes, 413 (MH)⁺.

EXAMPLE 80(3S)-[4-(3-Phenyl-morpholin-4-yl)-pyrimidin-2-yl]-(2-piperidin-1-yl-benzyl)-amine

Prepared as above using Intermediate 19(S) and 2-piperidinobenzylamine.

LCMS (ES⁺) Retention time 2.78 minutes, 430 (MH)⁺.

EXAMPLE 81(3S)-(2-Fluoro-benzyl)-[4-(3-Phenyl-morpholin-4-yl)-pyrimidin-2-yl]-amine

Prepared as above using Intermediate 19(S) and 2-fluorobenzylamine.

LCMS (ES⁺) Retention time 2.54 minutes, 365 (MH)⁺.

EXAMPLE 82(3S)-Naphthalen-1-ylmethyl-[4-(3-phenyl-morpholin-4-yl)-pyrimidin-2-yl]-amine

Prepared as above using Intermediate 19(S) andnaphthalen-1-ylmethylamine.

LCMS (ES⁺) Retention time 2.65 minutes, 397 (MH)⁺.

EXAMPLE 83(3S)-[4-(3-Phenyl-morpholin-4-yl)-pyrimidin-2-yl]-thiophen-2-ylmethyl-amine

Prepared as above using Intermediate 19(S) and thiophen-2-ylmethylamine.

LCMS (ES⁺) Retention time 2.50 minutes, 353 (MH)⁺.

EXAMPLE 34(3s)-(3-Methoxy-benzyl)-[4-(3-phenyl-morpholin-4-yl)-pyrimidin-2-yl]-amine

Prepared as above using Intermediate 19(S) and 3-methoxybenzylamine.

LCMS (ES⁺) Retention time 2.54 minutes, 377 (MH)⁺.

EXAMPLE 85(3S)-(4-Chloro-benzyl)-[4-(3-phenyl-morpholin-4-yl)-pyrimidin-2-yl]-amine

Prepared as above using Intermediate 19(S) and 4-chlorobenzylamine.

LCMS (ES⁺) Retention time 2.61 minutes, 381 (MH)⁺.

EXAMPLE 86(3S)-[4(3-Phenyl-morpholin-4-yl)-pyrimidin-2-yl]-(3-trifluoromethyl-benzyl)-amine

Prepared as above using Intermediate 19 and3-trifluoromethylbenzylamine.

LCMS (ES⁺) Retention time 2.65 minutes, 415 (MH)⁺.

EXAMPLE 87(3RS,1R)-3-(-Phenyl-4-[2-(1(R)-phenyl-ethylamino)-pyrimidin-4-yl]-piperazin-2-one

A solution of Intermediate 2, (200 mg, 0.69 mmol) in 2-ethoxyethanol(1.5 mL) was treated with (R)-α-methylbenzylamine (441 μL, 3.47 mmol)and sodium bicarbonate (291 mg, 3.47 mmol). The reaction mixture washeated at 120° for 30 hours, HPLC analysis showed the reaction to becomplete. After cooling the mixture was partitioned between DCM andwater (20 mL each), and further extracted with DCM (20 mL). The combinedorganic fractions were dried (MgSO₄) filtered and concentrated in vacuo.The residue was slurried with DCM and the resulting white solidcollected by filtration to give the title compound, 126 mg (49%).

δHNMR (d₃-MeOD): 7.63-7.60 (1H, m); 7.25-6.92 (10H, m); 5.82-5.80 (2H,m); 4.84-4.68 (1H, m); 3.71-3.65 (1H, m); 3.44-3.16 (3H, m); 1.29 and1.22 diastereomers (3H total, both d, J=7.0 Hz).

LCMS (ES⁺) Retention time 2.31mins 374 (MH)⁺.

EXAMPLE 88(3RS,1S)-3-Phenyl-4-[2-(1(S)-Phenyl-ethylamino)-pyrimidin-4-yl]-piperazin-2-one

Prepared using Intermediate 2 and (S)-α-methylbenzylamine according tothe method of Example 87. HPLC after 21 hours showed reaction to becomplete. The title compound was obtained as a white solid 115 mg (45%)

δH NMR (d₆-DMSO): 8.06 (1H, s), 7.63 (1H, d, J6.0 Hz); 7.21-6.98 (11H,m); 5.78 (1H, d, J6.0 Hz); 4.82 (1H, s); 3.75-3.65 (1H, m); 3.36-3.30(1H, m); 3.11-3.01 (2H, m); 1.23-1.15 (3H, m).

LCMS (ES⁺) Retention time 2.32mins 374 (MH)⁺.

EXAMPLE 89(3R*,1R)-3-Phenyl-4-[2-(1(R)-phenyl-ethylamino)pyrimidin-4-yl]-piperazin-2-one

The starting mixture of isomers was obtained as described in Example 87.60 mgs of the mixture was subjected to repeat flash columnchromatography to give the title compound as a single diastereomer 18 mg(60% recovery after chromatography).

δH NMR (d₃-MeOD): 7.69 (1H, d, J=6.2 Hz); 7.20-7.00 (10H, m); 6.10 (1H,s); 5.89 (1H, d, J6.2 Hz); 4.90 (1H, q, J=7.0 Hz); 3.79-3.72 (1H, m);3.44-3.36 (1H, m); 3.20-3.13 (2H, m); 1.37 (3H, d, J=7.0 Hz).

LCMS (ES⁺) Retention time 2.36mins 374 (MH)⁺.

EXAMPLE 90(3R*.1R)-3-Phenyl-4-[2-(1-phenyl-ethylamino)-pyrimidinyl-4-yl]-piperazin-2-one

To a degassed solution of Intermediate 21 (260 mg, 0.575 mmol) in MeOH(20 mL) and DCM (10 mL) was added 10% palladium on charcoal (100 mg).The mixture was stirred under an atmosphere of hydrogen for 2 hr. Themixture was filtered through Celite® and concentrated in vacuo. Theresidue was dissolved in 1% MeOH:DCM and washed with saturated sodiumbicarbonate solution, dried over magnesium sulphate and concentrated invacuo. Column chromatography (5-40% of (10% MeOHI/THF) into DCM-silica)yielded the title compound (36 mg).

δH NMR (d₃ MeOD): 7.73 (1H, d, J=6.2 Hz), 7.38-7.15 (10H, m), 7.10 (1H,m), 5.91 (1H, d, J=6.2 Hz), 4.80 (2H, m), 3.80 (1H, m), 3.50 (1H, m),3.35 (2H, m), 1.32 (3H, d, J=7.0 Hz).

LCMS (ES⁺) RT 2.357 minutes, 374 (MH)⁺.

EXAMPLE 914-[2-(1-Methyl-1-phenyl-ethylamino)pyrimidinyl-4yl]-3-phenyl-piperazin-2-one

The title compound (22 mg) was prepared in a similar manner to thecompound of Example 90, from cumylamine (550 mg, 4.08 mmol) andIntermediate 2 (300 mg, 0.816 mmol).

δH NMR (D₆ DMSO): 7.85 (1H, br-s), 7.53 (1H, d, J=5.9 Hz), 7.10-6.80(10H, m), 6.69 (1H, br-s), 5.67 (1H, d, J=5.9 Hz), 5.40-5.10 (1H, m),3.40 (1H, m), 3.00 (1H, m), 2.81 (1H, m), 1.37 (3H, s), 1.20 (3H, s).

LCMS (ES⁺) RT 2.384 minutes, 388 (MH)⁺.

EXAMPLE 924-[2-(2,6-Dichloro-benzylamino)-pyrimidin4-yl]-3-phenyl-piperazin-2-one

To a solution of Intermediate 2, (250 mg, 0.869 mmol) in ethoxyethanol(1.5 mL) were added 2,6-dichlorobenzylamine (760 mg, 4.34 mmol) andsodium bicarbonate (360 mg, 4.34 mmol). The mixture was stirred at 110°for 16 hr. The mixture was diluted with 1% MeOH:DCM and washed withwater and brine dried over magnesium sulphate and concentrated in vacuo.Column chromatography (2-15% MeOH-DCM-silica) yielded the title compound(95 mg).

δH NMR (d₆ DMSO): 8.08 (1H, br-s), 7.70 (1H, d, J=5.5 Hz)), 7.27-7.09(8H, m), 6.57 (1H, br-s), 5.87 (2H, m), 4.46 (2H, s), 3.75 (1H, m), 3.39(1H, m), 3.04 (2H, m).

LCMS (ES⁺) RT 2.419 minutes, 428 and 430 (MH)⁺.

EXAMPLE 93 4-(2-Benzyloxy-pyrimidin-4yl)-3phenyl-piperazin-2-one

To a solution of Intermediate 2, (100 mg, 0.348 mmol) in DMF (1 mL) wereadded benzylalcohol (75 mg, 0.695 mmol) and cesium carbonate (340 mg,1.04 mmol). The mixture was stirred at 1000 for 16 hr. The mixture wasconcentrated in vacuo. The residue was dissolved in 1% MeOH:DCM andwashed with water and brine, dried over magnesium sulphate andconcentrated in vacuo. Column chromatography (5-40% THF/DCM-silica)followed by preparative HPLC yielded the title compound (8 mg).

δH NMR (d₆ DMSO): 8.10 (1H, br-s), 7.86 (1H, d, J=6.0 Hz), 7.20-7.05(10H, m), 6.24 (1H, d, J=6.0), 5.65 (1H, m), 5.08 (1H, d, J=12.5 Hz),5.01 (1H, d, J=12.5 Hz), 3.77 (1H, m), 3.45 (1H, m), 3.25-3.00 (2H, m).

LCMS (ES⁺) RT 2.449 minutes, 361 (MH)⁺.

EXAMPLE 944-[2-(2,6-Dimethoxy-benzylamino)-pyrimidin-4-yl]-3-phenyl-piperazin-2-one

The title compound (149 mg) was prepared in a similar manner to thecompound of Example 92 from 2,6-dimethoxybenzylamine (726 mg, 4.34 mmol)and Intermediate 2, (250 mg, 0.869 mmol).

δH NMR (d₆ DMSO): 8.25 (1H, br-s), 7.82 (1H, br-s), 7.41-7.19 (8H, m),6.20 (2H, d, J=8.4 Hz), 6.07-5.75 (2H, m), 4.52 (1H, m), 4.35 (1H, m),3.90 (1H, m), 3.75 (6H, s), 3.55 (1H, m), 3.20 (1H, m).

LCMS (ES⁺) RT 2.368 minutes, 420 (MH)⁺.

EXAMPLE 95 4-(2-sec-Butylamino-pyrimidin-4-yl)-3-phenyl-piperazin-2-one

The title compound (134 mg) was prepared in a similar manner to thecompound of Example 92 from sec-butylamine (318 mg, 4.34 mmol) andIntermediate 2, (250 mg, 0.869 mmol).

δH (d₆ DMSO): 8.01 (1H, br-s), 7.58 (1H, d, J=5.8 Hz), 7.15-7.03 (5H,m), 6.11 (1H, d, J=5.8 Hz), 5.71 (2H, m), 3.73-3.28 (3H, m), 3.10 (1H,m), 2.95 (1H, m), 1.12-1.28 (2H, m), 0.82 (3H, d, J=6.6 Hz), 0.61 (3H,t, J=7.4 Hz).

LCMS (ES⁺) RT 2.216 minutes, 326 (MH)⁺.

EXAMPLES 96-110

The compounds of Examples 96-110 were made by sequential combination ofthe procedures described for Intermediate 21 and the compound of Example90, starting from Intermediate 20 and the appropriate amine.

EXAMPLE 964-[2-(3-Amino-benzylamino)-pyrimidin-4-yl]-3-phenyl-piperazin-2-one

From Intermediate 20 and 3-aminobenzylamine.

LCMS (ES⁺) RT 0.613 minutes, 375 (MH)⁺.

EXAMPLE 974-[2-(4-Methoxy-benzylamino)-pyrimidin-4-yl]-3-phenyl-piperazin-2-one

From Intermediate 20 and 4-methoxybenzylamine.

LCMS (ES⁺) RT 2.249 minutes, 390 (MH)⁺.

EXAMPLE 983-Phenyl-4-{2-[(Pyridin-2-ylmethyl)amino]-pyrimidin-4-yl}-piperazin-2-one

From Intermediate 20 and pyridin-2-yl-methylamine.

LCMS (ES⁺) RT 0.619 minutes, 361 (MH)⁺.

EXAMPLE 994-[2-(3-Fluoro-5-trifluoromethyl-benzylamino)-pyrimidin-4-yl]-3-phenyl-piperazin-2-one

From Intermediate 20 and 3-fluoro-5-trifluoromethylbenzylamine.

LCMS (ES⁺) RT 2.453 minutes, 446 (MH)⁺.

EXAMPLE 1004-[2-(4-Fluoro-3-trifluoromethyl-benzylamino)-pyrimidin-4-yl]-3-phenyl-piperazin-2-one

From Intermediate 20 and 4-fluoro-3-trifluoromethylbenzylamine.

LCMS (ES⁺) RT 2.455 minutes, 446 (MH)⁺.

EXAMPLE 1014-[2-2,6-Difluoro-benzylamino)-pyrimidin-4-yl-3-phenyl-piperazin-2-one

From Intermediate 20 and 2,6-difluorobenzylamine.

LCMS (ES⁺) RT 2.258 minutes, 396 (MH)⁺.

EXAMPLE 1024-[2-(2-Fluoro-benzylamino)-pyrimidin-4-yl]-3-phenyl-piperazin-2-one

From Intermediate 20 and 2-fluorobenzylamine.

LCMS (ES⁺) RT 2.269 minutes, 378 (MH)⁺.

EXAMPLE 1034-[2-(2,3-Dimethyl-benzylamino)-pyrimidin-4-yl]-3-Phenyl-piperazin-2-one

From Intermediate 20 and 2,3-dimethylbenzylamine.

LCMS (ES⁺) RT 2.396 minutes, 388 (MH)⁺.

EXAMPLE 1044-[2-(2,4-Dimethoxy-benzylamino)-pyrimidin-4-yl]-3-phenyl-piperazin-2-one

From Intermediate 20 and 2,4-dimethoxybenzylamine.

LCMS (ES⁺) RT 2.319 minutes, 420 (MH)⁺.

EXAMPLE 1053-Phenyl-4-{2-[(Pyridin-3-ylmethyl)-amino]-pyrimidin-4-yl]-piperazin-2-one

From Intermediate 20 and pyridin-3-yl-methylamine.

LCMS (ES⁺) RT 3.910 minutes, 36 1(MH)⁺.

EXAMPLE 1064-[2-(3,4-Dihydro-1H-isoquinolin-2-yl)-pyrimidin-4-yl]-3-phenyl-piperazln-2-one

From Intermediate 20 and 1,2,3,4-tetrahydroisoquinoline.

LCMS (ES⁺) RT 2.336 minutes, 386 (MH)⁺.

EXAMPLE 1073-Phenyl-4-[2-(1-phenyl-ethylamino)-pyrimidin-4-yl]-piperazin-2-one

From Intermediate 20 and α-methylbenzylamine (racemic).

LCMS (ES⁺) RT 2.300 minutes, 374 (MH)⁺.

EXAMPLE 1084-[2-(3-Methyl-benzylamino)pyrimidin-4-yl]-3-phenyl-piperazin-2-one

From Intermediate 20 and 3-methylbenzylamine.

LCMS (ES⁺) RT 2.318 minutes, 374 (MH)⁺.

EXAMPLE 1094-{2-[(Furan-2-ylmethyl)-amino]-pyrimidin-4-yl}-3-phenyl-piperazin-2-one

From Intermediate 20 and furan-2-yl-methylamine.

LCMS (ES⁺) RT 2.034 minutes, 350(MH)⁺.

EXAMPLE 1103-Phenyl-4-{2-[(thiophen-2-ylmethyl)amino]-pyrimidin-4yl}-piperazin-2-one

From Intermediate 20 and thiophene-2-yl-methylamine.

LCMS (ES⁺) RT 2.158 minutes, 366(MH)⁺.

EXAMPLES 111-116

The compounds of Examples 111-116 were prepared according to thefollowing procedure.

Intermediate 2, (250 mgs, 0.87 mmol) was dissolved in dimethoxyethane(3.5 mL) and an inert atmosphere of nitrogen was introduced. To this wasadded the appropriate boronic acid (1.5 eq, 1.31 mmol), sodium carbonate(2 eq, 230 mg, 1.74 mmol), and palladium (tetrakis)-triphenylphosphine(10 mol %, 100 mg, 0.09 mmol). The resulting suspensions were heated atreflux overnight. TLC or LCMS showed reactions to be complete. The crudereaction mixture was partitioned between DCM (10 mL) and water (3 mL).This mixture was passed through a phase separating filter-frit andorganic phase concentrated in vacuo. Purification to yield the titlecompound was achieved by using the Isco combi-flash.

EXAMPLE 111 3-Phenyl-4-(2-phenyl-pyrimidin-4-yl)-piperazin-2-one

From Intermediate 2 and phenyl boronic acid

δH NMR (d₃-MeOD): 8.21 (1H, d, J=6.2 Hz); 8.15-8.13 (2H, m); 7.40-7.21(8H, m); 6.58 (1H, d, J=6.2 Hz); 6.18 (1H, s); 4.03-4.00 (1H, m);3.82-3.79 (1H, m); 3.47-3.35 (2H, m).

LCMS (ES⁺) Retention time 2.13mins 331 (MH)⁺.

EXAMPLE 1123-[4-(3Oxo-2-phenyl-piperazin-1-yl)-pyrimidin-2-yl-benzonitrile

From Intermediate 2 and 3-cyanophenyl boronic acid

δH NMR (d₃-MeOD): 8.45-8.43 (2H, m); 8.26 (1H, d, J=6.2 Hz); 7.71-7.69(1H, m); 7.54-7.50 (1H, m); 7.41-7.39 (2H, m); 7.30-7.20 (3H, m); 6.64(1H, d, J=6.2 Hz); 6.09 (1H, S); 4.04-4.02 (1H, m); 3.85-3.79 (1H, m);3.50-3.37 (2H, m).

LCMS (ES⁺) Retention time 2.79mins 356 (MH)⁺ and 378 (MNa)⁺.

EXAMPLE 1134-[4-(3-Oxo-2-phenyl-piperazin-1-yl)-pyrimidin-2-yl]-benzonitrile

From Intermediate 2 and 4-cyanophenyl boronic acid

δH NMR (d₃-MeOD): 8.32 (1H, d, J=8.5 Hz); 3.48-3.37 (2H, m); 8.27 (1H,d, J=6.2 Hz); 7.70-7.68 (2H, m); 7.40-7.21 (5H, m); 6.64 (1H, d, J=6.2Hz); 6.12 (1H, s); 4.03-4.00 (1H, m); 3.83-3.79 (2H, m).

LCMS (ES⁺) Retention time 2.80 mins 356 (MH)⁺ and 378 (MNa)⁺.

EXAMPLE 1144-[2-(4-Chloro-phenyl)-pyrimidin-4-yl]-3-phenyl-piperazin-2-one

From Intermediate 2 and 4-chlorophenyl boronic acid.

δH NMR (d₃-MeOD): 8.21 (1H, d, J=6.2 Hz); 8.14-8.12 (2H, m); 7.40-7.21(7H, m); 6.59 (1H, d, J=6.2 Hz); 6.12 (1H, s); 4.03-4.00 (1H, m);3.83-3.79 (1H, m); 3.37-3.45 (2H, m).

LCMS (ES⁺) Retention time 2.75mins 365 (³⁵Cl, MH)⁺ and 367 (³⁷Cl, MH)⁺.

EXAMPLE 1154-[2-(3-Chloro-phenyl)-pyrimidin-4-yl]-3-phenyl-piperazin-2-one

From Intermediate 2 and 3-chlorophenyl boronic acid.

δH NMR (d₃-MeOD): 8.23 (1H, d, J=6.2 Hz); 8.13-8.06 (2H, m); 7.41-7.20(7H, m); 6.61 (1H, d, J=6.2 Hz); 6.11 (1H, s); 4.00-3.96 (1H, m);3.83-3.79 (1H, m); 3.48-3.37 (2H, m).

LCMS (ES⁺) Retention time 2.99mins 365 (³⁵Cl, MH)⁺ and 367 (³⁷Cl, MH)⁺.

EXAMPLE 116 4-[2-(1H-Indol-5-yl)-pyrimidin-4yl]-3-phenyl-piperazin-2-one

From Intermediate 2 and 5-indolyl boronic acid.

δH NMR (d₃-MeOD): 8.41 (1H, d, J=1.0 Hz); 8.17 (1H, d J6.2 Hz); 7.96(1H, dd, J8.6. 1.6 Hz); 7.44-7.41 (2H, m); 7.32-7.16 (5H, m); 6.50 (1H,d, J=6.2 Hz); 6.42 (1H, dd, J=3.2, 0.9 Hz); 6.26 (1H, s); 4.07-4.00 (1H,m); 3.83-3.74 (2H, m); 3.51-3.33 (2H, m).

LCMS (ES⁺) Retention time 2.21 mins 370 (MH)⁺.

The following assays and animal models can be used to demonstrate thepotency and selectivity of the compounds according to the invention. Ineach assay an IC50 value was determined for each test compound andrepresents the concentration of compound necessary to achieve 50%inhibition.

Preparation of Activated Human D380 for Inhibitor Assays.

Purification of Human p38α

Human p38α, incorporating an N-terminal (His)6 tag, was expressed inbaculovirus-infected High-Five™ cells (Invitrogen) according to themanufacturers instructions. The cells were harvested 72 h post-infectionand lysed in phosphate buffered saline (PBS) containing 1% (w/v)β-octylglucoside and Complete, EDTA-free™ protease inhibitors (RocheMolecular Biochemicals). The lysate was centrifuged at 35000×g for 30min at 4° C. and the supernatant applied to a NiNTA™ column (Qiagen).Bound protein was eluted by 150 mM imidazole in PBS (after a wash with15 mM imidazole in PBS) and directly applied to a HiTrap Q™ column (APBiotech). Bound protein was eluted using a 20 column volume, 0 to 1MNaCl gradient. Fractions containing (His)6-p38 were aliquotted andstored at −70° prior to their activation.

Preparation of GST-MKK6EE-Containing Lysates

E. coli (BL21 pLysS) expressing the constituitively activated form ofhuman MKK6 fused with an N-terminal glutathione-S-transferase tag(GST-MKK6EE) were harvested by centrifugation and frozen at −70°. Cellswere lysed by resuspension in {fraction (1/10)}th the culture volume ofPBS containing Complete, EDTA-free™ protease inhibitors followed bysonication on ice for 4×15 sec. Cell debris was removed bycentrifugation at 35,000×g and the resultant supernatant stored inaliquots at −70°.

Activation of (His)6-D38

0.45 mL of purified (His)6-p38 was incubated with 50 μL of theGST-MKK6EE-containing lysate for 30 min at 23° in the presence of 1 mMβ-glycerophosphate, 10 mM MgCl₂ and 9 mM ATP. The extent of activationwas monitored by mass spectrometric detection of thedoubly-phosphorylated form of (His)6-p38, which routinely comprisedgreater than 90% of the final (His)6p38 preparation. The activated(His)6-p38 was then diluted ×10 in PBS and repurified using the methoddescribed above. The concentration of purified, activated (His)6-p38 wasmeasured by UV absorbance at 280 nm using A280,0.1%=1.2 and thepreparation stored in aliquots at −70° prior to its use in inhibitorassays.

p38 Inhibition Assays

Inhibition of Phosphorylation of Biotinylated Myelin Basic Protein (MBP)

The inhibition of p38 catalysed phosphorylation of biotinylated MBP ismeasured using a DELFIA based format. The assay was performed in abuffer comprising, 20 mM HEPES (pH 7.4), 5 mM MgCl₂ and 3 mM DTT. For atypical IC50 determination, biotinylated MBP (2.5 μM) was incubated atroom temperature in a streptavidin-coated microtitre plate together withactivated gst-p38 (10 nM) and ATP (1 μM) in the presence of a range ofinhibitor concentrations (final concentration of DMSO is 2 percent).After fifteen minutes the reaction was terminated by the addition ofEDTA (75 mM). The microtitre plate was then washed with Tris bufferedsaline (TBS), prior to the addition of 100 μl of anti-phospho MBPantibody (mouse) together with europium-labeled anti-mouse IgG antibody.After one hour at room temperature the plate was again washed in TBSfollowed by the addition of Enhancement solution (PerkinElmer Wallac).Fluorescence measurements were performed after a further fifteen minutesat room temperature.

IC50 values are determined from the plot of Log₁₀ inhibitorconcentration (x-axis) versus percentage inhibition of the fluorescencegenerated by a control sample in the absence of inhibitor (y-axis).

Purification of Human Peripheral Bood Mononuclear Cells

Peripheral blood mononuclear cells (PBMC) were isolated from normalhealthy volunteers. Whole blood was taken by venous puncture usingheparinised vacutainers (Becton Dickinson), diluted 1 in 4 in RPMI 1640(Gibco, UK) and centrifuged at 400 g for 35 min over a Ficoll-paquegradient (Amersham-Pharmacia Biotech, UK). Cells at the interface wereremoved and washed once followed by a low speed spin (250 g) to removeplatelets. Cells were then resuspended in DMEM containing 10% FCS,penicillin 100 units ml⁻¹, streptomycin 50 μg ml⁻¹ and glutamine 2 mM(Gibco, UK).

Inhibitor Dilutions

Inhibitor stocks (20 mM) were kept as a frozen solution (−20° C.) inDMSO. Serial dilutions of inhibitors were performed in DMSO as 250-timesconcentrated stocks. Inhibitors were diluted 1 in 250 into tissueculture media, prewarmed to 37° C. and transferred to plates containingPBMC. PBMC and inhibitors were incubated together for 30 mins prior toaddition of LPS. Inhibitors used in whole blood assays were preparedaccording to a different regime. Using the same stock solution serialdilutions of inhibitors were performed in DMSO. Inhibitors were thendiluted 1 in 500 straight into whole blood in a volume of 1 μL.Inhibitor was incubated with whole blood for 30 mins prior to theaddition of LPS.

LPS Stimulation of PBMC

PBMC were resuspended at a density of 2×10⁵ cells/well in flat bottomed96 well tissue culture treated plates. After the addition of inhibitorcells were stimulated with an optimal dose of LPS (E coli strain B5:055,Sigma, at a final concentration of 1 μg ml⁻¹) and incubated at 37° C. in5% CO₂/95% air for 18 hours. TNF-α levels were measured from cell freesupernatants by sandwich ELISA (BioSource #CHC1751).

LPS Stimulation of Whole Blood

Whole blood was taken by venous puncture using heparinised vacutainers(Becton Dickinson), and 500 μl of blood aliquoted into each well of a 24well tissue culture treated plate. After the addition of inhibitor cellswere stimulated with an optimal dose of LPS (E coli strain B5:055,Sigma, at a final concentration of 1 μg ml⁻¹) and incubated at 37° C.without CO₂ for 18 hours. TNF-α levels were measured from cell freesupernatants by sandwich ELISA (BioSource #CHC1751).

Rat LPS Induced TNF Release

Male Lewis rats (180-200 g) are anaesthetised with Isofluor and injectedi.v. with LPS* in a volume of 0.5 ml sterile saline. After 90 minutesblood is collected into EDTA tubes for preparation of plasma samples.Plasma is stored at −70° C. prior to assay for TNFα by commercial ELISA.

Rat CIA

Female Lewis rats (180-200 g) are anaesthetised with Isofluor andimmunised i.d. at the base of the tail with 2×100 μl of emulsioncontaining 4 mg/ml bovine collagen II in 0.01M acetic acid and Freund'sIncomplete Adjuvant at a ratio of 1:1.

A polyarthetis develops with onset from about 13 days postsensitisation.

The disease is mainly confined to the ankles and is quantified byplethysmometry. Results are expressed as change in paw volume over time.

In the p38 inhibitor assay compounds of the invention have IC₅₀ valuesof around 30 μM and below. In particular compounds of the Examples haveIC₅₀ values of 5 μM and below with the most active compounds having IC₅₀values of 500 nM and below. The compounds of the invention are clearlypotent inhibitors of p38 kinase, especially p38α kinase.

1. A compound of formula (1):

wherein: R^(a) and R^(b) are each independently a hydrogen atom or agroup R^(c), or R^(a) and R^(b) together form an oxo (═O) or thio (═S)group; X is a N atom or an optionally substituted CH group; Y is a —O—or —S— atom or —SO— or —SO₂— group or an optionally substituted —CH₂— or—NH— group with the proviso that when R^(a) and R^(b) together form anoxo (═O) or thio (═S) group, Y is an optionally substituted —CH₂— or—NH— group; L¹ is a covalent bond or a linker atom or group; p is zeroor the integer 1; Alk¹ is an optionally substituted C₁₋₁₀aliphatic orC₁₋₁₀heteroaliphatic chain; R¹ is a hydrogen or halogen atom or a —CN,—NO₂ or optionally substituted C₃₋₁₀cycloaliphatic,C₇₋₁₀polycycloaliphatic, C₂₋₁₀heterocycloaliphatic,C₆₋₁₀heteropolycycloaliphatic, C₆₋₁₂aromatic or C₁₋₉heteroaromaticgroup, with the proviso that when L¹ is a covalent bond and p is zero.R¹ is other than a hydrogen or halogen atom or a —CN or —NO₂ group; n iszero or the integer 1, 2 or 3 with the proviso that when n is zero, Y isan optionally substituted —CH₂— group; Ar is an optionally substitutedC₆₋₁₂aromatic or C₁₋₉heteroaromatic group; m is zero or the integer 1, 2or 3; R^(c), which may be present on any carbon or, where available,nitrogen atom in the Y-containing ring, is an oxo (═O) or thio (═S) atomor an atom or group -(Alk²)_(r)(R⁵)_(s); Alk² is an optionallysubstituted C₁₋₁₀aliphatic or C₁₋₁₀heteroaliphatic chain; r is zero orthe integer 1; s is the integer 1, 2 or 3; and R⁵ is a hydrogen orhalogen atom or a hydroxyl (—OH), thiol (—SH), cyano (—CN), —CO₂R—OCO₂R², —CONR²R³ —OCONR²R³, —CSNR²R³, nitro (—NO₂), amino (—NH₂),—NHR₂, —N(R²)(R³), —COR², —OCOR², —N(R³)COR², —N(R³)CSR², —SO₂N(R²)(R³),—N(R²)SO₂R³, —N(R⁴)CON(R²)(R³) —N(R⁴)CSN(R²)(R³), —N(R⁴)SO₂N(R²)(R³),C₃₋₁₀cycloaliphatic, C₂₋₁₀heterocycloaliphatic, C₆₋₁₂aromatic orC₁₋₉heteroaromatic group; R² is a hydrogen atom or an optionallysubstituted C₁₋₆alkyl C₆₋₁₂aromatic or C₁₋₉heteroaromatic group, R³ is ahydrogen atom or an optionally substituted C₁₋₆alkyl group or togetherwith the N atom to which they are attached R² and R³ alkyl groups arejoined to form a heterocyclic ring which may be optionally interruptedby a further —O— or —S— atom or —N(R²)— group: R⁴ is a hydrogen atom oran optionally substituted C₁₋₆alkyl group, q is zero or the integer 1 or2; R^(d) is a hydrogen or halogen atom or a C₁₋₆alkyl, haloC₁₋₆alkyl,hydroxyl (—OH), C₁₋₆alkoxy, haloC₁₋₆alkoxy, thiol (—SH), C₁₋₆alkylthio,cyano (—CN), —CO₂R⁶, —OCO₂R⁶, —CONR⁶R⁷, —OCONR⁶R⁷, —CSNR⁶R⁷, nitro(—NO₂), amino (—NH₂), —NHR⁶, —N(R⁶)(R⁷), —COR⁶, —OCOR⁶, —N(R⁷)COR⁶,—N(R⁷)CSR⁶, —SO₂N(R⁶)(R⁷), —N(R⁶)SO₂R⁷, —N(R⁸)CON(R⁶)(R⁷),—N(R⁸)CSN(R⁶)(R⁷) or —N(R⁸)SO₂N(R⁶)(R⁷) group; R⁶ is a hydrogen atom oran optionally substituted C₁₋₆alkyl group; R⁷ is a hydrogen atom or anoptionally substituted C₁₋₆alkyl group or together with the N atom towhich they are attached R⁶ and R⁷ alkyl groups are joined to form aheterocyclic ring which may be optionally interrupted by a further —O—or —S— atom or —N(R⁶)— group; R⁸ is a hydrogen atom or an optionallysubstituted C₁₋₆alkyl group; and the salts, solvates, hydrates andN-oxides thereof.
 2. A compound according to claim 1 in which R^(a) andR^(b) is each independently a hydrogen atom or together form an oxo (═O)or thio (═S) group.
 3. A compound according to claim 2 in which R^(a)and R^(b) together form an oxo (═O) group.
 4. A compound according toclaim 1 in which Y is a —NH— or —N(CH₃)— group.
 5. A compound accordingto claim 1 in which X is a N atom.
 6. A compound according to claim 1 inwhich n is the integer
 1. 7. A compound according to claim 1 in which L¹is a covalent bond or an —O— or —S— atom or an —N(R¹⁰)—, —C(O)—, —C(S)—,—S(O)— or —S(O)₂— group and R¹⁰ is a hydrogen atom or a straight orbranched C₁₋₆alkyl group.
 8. A compound according to claim 7 in which L¹is a covalent bond, an —O— or —S— atom or a —NH— group.
 9. A compoundaccording to claim 8 wherein L¹ is a —NH— group.
 10. A compoundaccording to claim 1 in which R¹ is a hydrogen atom or an optionallysubstituted C₃₋₁₀cycloaliphatic, C₂₋₁₀heterocycloaliphatic,C₆₋₁₂aromatic or C₁₋₉heteroaromatic group.
 11. A compound according toclaim 10 in which R¹ is an optionally substituted C₃₋₇cycloalkyl,C₂₋₇heterocycloalkyl or C₆₋₁₂aromatic group.
 12. A compound according toclaim 11 wherein R¹ is an optionally substituted phenyl group.
 13. Acompound according to claim 1 in which p is the integer 1 and Alk¹ is anoptionally substituted C₁₋₃alkylene chain.
 14. A compound according toclaim 1 in which m is zero.
 15. A compound according to claim 1 in whichAr is an optionally substituted phenyl group.
 16. A compound accordingto claim 15 in which Ar is a phenyl group.
 17. A compound which is:3-Phenyl-4-[2-(3-trifluoromethyl-benzylamino)-pyrimidin-4-yl]-piperazin-2-one;3-[4-(4-Methyl-3-oxo-2-phenyl-piperazin-1-yl)-pyrimidin-2-ylamino]-benzonitrile;3-[4-(4-Cyclopropylmethyl-3-oxo-2-phenyl-piperazin-1-yl)-pyrimidin-2-ylamino]-benzonitrile;3-[4-(4-Benzyl-3-oxo-2-phenyl-piperazin-1-yl)-pyrimidin-2-ylamino]-benzonitrile;3-[4-(4-Allyl-3-oxo-2-phenyl-piperazin-1-yl)-pyrimidin-2-ylamino]-benzonitrile:3-[4-(2-Phenyl-piperidin-1-yl)-pyrimidin-2-ylamino]-benzonitrile;Phenyl-[4-(2-phenyl-piperidin-1-yl)-pyrimidin-2-yl]-amine;Benzyl-[4-(2-phenyl-piperidin-1-yl)-pyrimidin-2-yl]-amine;(3R)-(3-Chloro-phenyl)-[4-(3-phenyl-morpholin-4-yl)-pyrimidin-2-yl]-amine;(3R)-(2,6-Difluoro-benzyl)-[4-(3-phenyl-morpholin-4-yl)-pyrimidin-2-yl]-amine;(1R,3R)-(1-Phenyl-ethyl)-[4-(3-phenyl-morpholin-4-yl)-pyrimidin-2-yl]-amine;(3R,1S)-(1-Phenyl-ethyl)-[4-(3-phenyl-morpholin-4-yl)-pyrimidin-2-yl]-amine;3-(4-Fluoro-phenyl)-4-[2-(4-nitro-phenylamino)-pyrimidin-4-yl]-piperazin-2-one;3-(4-Fluoro-phenyl)-4-[2-(4-fluoro-3-trifluoromethyl-phenylamino)-pyrimidin-4-yl]-piperazin-2-one:(3-Chloro-phenyl)-[4-(2-phenyl-piperazin-1-yl)-pyrimidin-2-yl]-amine;4-(2-Benzylaminopyrimidin-4-yl)-3-phenyl-piperazin-2-one;3-Phenyl-4-(2-phenylaminopyrimidin-4-yl)-piperazin-2-one;4-[2-(2-Methylphenylamino)pyrimidin-4-yl]-3-phenyl-piperazin-2-one;4-[2-(3-Methylphenylamino)pyrimidin-4-yl]-3-phenyl-piperazin-2-one;4-[2-(3-Cyanophenylamino)pyrimidin-4-yl]-3-phenyl-piperazin-2-one;4-[2-(3-Nitrophenylamino)pyrimidin-4-yl]-3-phenyl-piperazin-2-one;4-[2-(4-Cyano-phenylamino)pyrimidin-4-yl]-3-phenyl-piperazin-2-one;4-[2-(4-Methoxyphenylamino)pyrimidin-4-yl]-3-phenyl-piperazin-2-one;4-[2-(2-Methoxyphenylamino)pyrimidin-4-yl]-3-phenyl-piperazin-2-one;4-[2-(3-Methoxy-phenylamino)pyrimidin-4-yl]-3-phenyl-piperazin-2-one;4-[2-(3,4,5-trimethoxyphenylamino)pyrimidin-4-yl]-3-phenyl-piperazin-2-one;4-[2-(4-Chlorophenylamino)pyrimidin-4-yl]-3-phenyl-piperazin-2-one;4-[2-(3-Chlorophenylamino)pyrimidin-4-yl]-3-phenyl-piperazin-2-one;4-[2-(3-Fluorophenylamino)pyrimidin-4-yl]-3-phenyl-piperazin-2-one;4-[2-(2-Fluorophenylamino)pyrimidin-4-yl]-3-phenyl-piperazin-2-one;4-[2-(4-Fluorophenylamino)pyrimidin-4-yl]-3-phenyl-piperazin-2-one;4-[2-(1,3-Dimethyl-butylamino)-pyrimidin-4-yl]-3-phenyl-piperazin-2-one;3-Phenyl-4-[2-(3,3,3-trifluoro-propylamino)-pyrimidin-4-yl]-piperazin-2-one;4-[2-(3-Methoxy-propylamino)-pyrimidin-4-yl]-3-phenyl-piperazin-2-one;4-[2-(3-Isopropoxy-propylamino)-pyrimidin-4-yl]-3-phenyl-piperazin-2-one;4-(2-Allylamino-pyrimidin-4-yl)-3-phenyl-piperazin-2-one;4-[2-(Cyclopropylmethyl-amino)-pyrimidin-4-yl]-3-phenyl-piperazin-2-one;(3R)-[4-(3-Phenyl-morpholin-4-yl)-pyrimidin-2-yl]-thiophen-2-ylmethyl-amine;4-[2-(2-Methoxy-ethylamino)-pyrimidin-4-yl]-3-phenyl-piperazin-2-one;4-(2-Isobutylamino-pyrimidin-4-yl)-3-phenyl-piperazin-2-one;{4-[4-(3-Oxo-2-phenyl-piperazin-1-yl)-pyrimidin-2-ylamino]-butyl}-carbamicacid tert-butyl ester;4-(2-Pentylamino-pyrimidin-4-yl)-3-phenyl-piperazin-2-one;4-(2-Cyclopentylamino-pyrimidin-4-yl)-3-phenyl-piperazin-2-one;4-[2-(3-Methyl-butylamino)-pyrimidin-4-yl]-3-phenyl-piperazin-2-one;(3R)-(2,3-Difluoro-benzyl)-[4-(3-phenyl-morpholin-4-yl)-pyrimidin-2-yl]-amine;3-Phenyl-4-[2-(3-phenyl-propylamino)-pyrimidin-4-yl]-piperazin-2-one;3-Phenyl-4-[2-(4-phenyl-butylamino)-pyrimidin-4-yl]-piperazin-2-one;4-[2-(1-Methyl-butylamino)-pyrimidin-4-yl]-3-phenyl-piperazin-2-one;4-(2-Phenethylamino-pyrimidin-4-yl)-3-phenyl-piperazin-2-one;(3R)Indan-1-yl-[4-(3-phenyl-morpholin-4-yl)-pyrimidin-2-yl]-amine;4-{2-[2-(4-Hydroxy-phenyl)-ethylamino]-pyrimidin-4-yl]-3-phenyl-piperazin-2-one;4-(2-Cyclobutylamino-pyrimidin-4-yl)-3-phenyl-piperazin-2-one;4-[2-(2-Methyl-butylamino)-pyrimidin-4-yl]-3-phenyl-piperazin-2-one;4-{2-[2-(5-Methoxy-1H-indol-3-yl)-ethylamino]-pyrimidin-4-yl}-3-phenyl-piperazin-2-one;4-{2-[2-(1H-Indol-3-yl)-ethylamino]-pyrimidin-4-yl}-3-phenyl-piperazin-2-one;4-[2-(2-Diethylamino-ethylamino)-pyrimidin-4-yl]-3-phenyl-piperazin-2-one;(3S)-Benzo[b]thiophen-3-ylmethyl-[4-(3-phenyl-morpholin-4-yl)-pyrimidin-2-yl]-amine;(3S)-[4-(3-Phenyl-morpholin-4-yl)-pyrimidin-2-yl]-(1,3,5-trimethyl-1H-pyrazol-4-ylmethyl)-amine;(3S)-(2,4-Dichloro-benzyl)-[4-(3-phenyl-morpholin-4-yl)-pyrimidin-2-yl]-amine;(3S)-(1-Methyl-1H-pyrrol-2-ylmethyl)-[4-(3-phenyl-morpholin-4-yl)-pyrimidin-2-yl]-amine;(3S)-[4-(3-Phenyl-morpholin-4-yl)-pyrimidin-2-yl]-(1,2,3,4-tetrahydro-naphthalen-1-yl)-amine;(3S)-Indan-1-yl-[4-(3-phenyl-morpholin-4-yl)-pyrimidin-2-yl]-amine;(3S)-(2-Chloro-benzyl)-[4-(3-phenyl-morpholin-4-yl)-pyrimidin-2-yl]-amine;(3S)-(2,4-Dichloro-benzyl)-[4-(3-phenyl-morpholin-4-yl)-pyrimidin-2-yl]-amine;(3S)-(2-Methoxy-benzyl)-[4-(3-phenyl-morpholin-4-yl)-pyrimidin-2-yl]-amine;(3S)-(2-Methyl-benzyl)-[4-(3-phenyl-morpholin-4-yl)-pyrimidin-2-yl]-amine;(3S)-(2,5-Difluoro-benzyl)-[4-(3-phenyl-morpholin-4-yl)-pyrimidin-2-yl]-amine;(3S)-[4-(3-Phenyl-morpholin-4-yl)-pyrimidin-2-yl]-(2-trifluoromethyl-benzyl)-amine:(3S)-(2-Chloro-6-fluoro-benzyl)-[4-(3-phenyl-morpholin-4-yl)-pyrimidin-2-yl]-amine:(3S)-(2,3-Dichloro-benzyl)-[4-(3-phenyl-morpholin-4-yl)-pyrimidin-2-yl]-amine:(3S)-(2-Chloro-6-methyl-benzyl)-[4-(3-phenyl-morpholin-4-yl)-pyrimidin-2-yl]-amine;(3S)-(4-Fluoro-2-trifluoromethyl-benzyl)-[4-(3-phenyl-morpholin-4-yl)-pyrimidin-2]-amine;(3S)-(2,3-Difluoro-benzyl)-[4-(3-phenyl-morpholin-4-yl-pyrimidin-2-yl]-amine:(3S)-(2,3-Dimethyl-benzyl)-[4-(3-phenyl-morpholin-4-yl)-pyrimidin-2-yl]-amine:(3S)-(2-Nitro-benzyl)-[4-(3-phenyl-morpholin-4-yl)-pyrimidin-2yl]-amine;(3S)-[4-(3-Phenyl-morpholin-4-yl)-pyrimidin-2-yl]-(2,3,4-trifluoro-benzyl)-amine;(3S)-[4-(3-Phenyl-morpholin-4-yl)-pyrimidin-2-yl]-(2,3,6-trifluoro-benzyl)-amine:(3S)-(2-Methylsulfanyl-benzyl)-[4-(3-phenyl-morpholin-4-yl)-pyrimidin-2-yl]-amine:(3S)-(6-Chloro-2-fluoro-3-methyl-benzyl)-[4-(3-phenyl-morpholin-4-yl)-pyrimidin-2-yl]-amine;(3S)-[4-(3-Phenyl-morpholin-4-yl)-pyrimidin-2-yl]-(2-piperidin-1-yl-benzyl)-amine;(3S)-(2-Fluoro-benzyl)-[4-(3-phenyl-morpholin-4-yl)-pyrimidin-2-yl]-amine;(3S)-Naphthalen-1-ylmethyl-4-(3-phenyl-morpholin-4-yl)-pyrimidin-2-yl]-amine:(3S)-[4-(3-Phenyl-morpholin-4-yl)-pyrimidin-2-yl]-thiophen-2-ylmethyl-amine;(3S)-(3-Methoxy-benzyl)-[4-(3-phenyl-morpholin-4-yl)-pyrimidin-2-yl]-amine;(3S)-(4-Chloro-benzyl)-[4-(3-phenyl-morpholin-4-yl)-pyrimidin-2-yl]-amine;(3S)-[4-(3-Phenyl-morpholin-4-yl)-pyrimidin-2-yl]-(3-trifluoromethyl-benzyl)-amine;(3RS,1R)-3-(-Phenyl-4-[2-(1(R)-phenyl-ethylamino)-pyrimidin-4-yl]-piperazin-2-one;(3RS,1S)-3-Phenyl-4-[2-(1(S)-phenyl-ethylamino)-pyrimidin-4-yl]-piperazin-2-one;(3R*,1R)-3-Phenyl-4-[2-(1(R)-phenyl-ethylamino)-pyrimidin-4-yl]-piperazin-2-one;(3R*,1R)-3-Phenyl-4-[2-(1-phenyl-ethylamino)-pyrimidin-4-yl]-piperazin-2-one;4-[2-(1-Methyl-1-phenyl-ethylamino)-pyrimidin-4-yl]-3-phenyl-piperazin-2-one;4-[2-(2,6-Dichloro-benzylamino)-pyrimidin-4-yl]-3-phenyl-piperazin-2-one;4-(2-Benzyloxy-pyrimidin-4-yl)-3-phenyl-piperazin-2-one;4-[2-(2,6-Dimethoxy-benzylamino)-pyrimidin-4-yl]-3-phenyl-piperazin-2-one;4-(2-sec-Butylamino-pyrimidin-4-yl)-3-phenyl-piperazin-2-one;4-[2-(3-Amino-benzylamino)-pyrimidin-4-yl]-3-phenyl-piperazin-2-one;4-[2-(4-Methoxy-benzylamino)-pyrimidin-4-yl]-3-phenyl-piperazin-2-one;3-Phenyl-4-{2-[(pyrimidin-2-ylmethyl)-amino]-pyrimidin-4-yl]-piperazin-2-one;4-[2-(3-Fluoro-5-trifluoromethyl-benzylamino)-pyrimidin-4-yl]-3-phenyl-piperazin-2-one;4-[2-(4-Fluoro-3-trifluoromethyl-benzylamino)-pyrimidin-4-yl]-3-phenyl-piperazin-2-one;4-[2-(2,6-Difluoro-benzylamino)-pyrimidin-4-yl]-3-phenyl-piperazin-2-one;4-[2-(2-Fluoro-benzylamino)-pyrimidin-4-yl]-3-phenyl-piperazin-2-one;4-[2-(2,3-Dimethyl-benzylamino)-pyrimidin-4-yl]-3-phenyl-piperazin-2-one;4-[2-(2,4-Dimethoxy-benzylamino)-pyrimidin-4-yl]-3-phenyl-piperazin-2-one;3-Phenyl-4-{2-[(pyridin-3-ylmethyl)-amino]-pyrimidin-4-yl}-piperazin-2-one;4-[2-(3,4-Dihydro-1H-isoquinolin-2-yl)-pyrimidin-4-yl]-3-phenyl-piperazin-2-one;3-Phenyl-4-[2-(1-phenyl-ethylamino)-pyrimidin-4-yl]-piperazin-2-one;4-[2-(3-Methyl-benzylamino)-pyrimidin-4-yl]-3-phenyl-piperazin-2-one;4-{2-[(Furan-2-ylmethyl)-amino]-pyrimidin-4-yl}-3-phenyl-piperazin-2-one;3-Phenyl-4-{2-[(thiophen-2-ylmethyl)-amino]-pyrimidin-4-yl}-piperazin-2-one;3-Phenyl-4-(2-phenyl-pyrimidin-4-yl)-piperazin-2-one;3-[4-(3-Oxo-2-phenyl-piperazin-1-yl)-pyrimidin-2-yl]-benzonitrile;4-[4-(3-Oxo-2-phenyl-piperazin-1-yl)-pyrimidin-2-yl]-benzonitrile;4-[2-(4-Chloro-phenyl)-pyrimidin-4-yl]-3-phenyl-piperazin-2-one;4-[2-(3-Chloro-phenyl)-pyrimidin-4-yl]-3-phenyl-piperazin-2-one; or4-[2-(1H-Indol-5-yl)-pyrimidin-4-yl]-3-phenyl-piperazin-2-one; and thesalts, solvates, hydrates and N-oxides thereof.
 18. A pharmaceuticalcomposition comprising a compound according to claim 1 together with oneor more pharmaceutically acceptable carriers, excipients or diluents.